Hormonal, immune, and oxidative stress responses to blood flow‐restricted exercise

M H Hjortshoej; P Aagaard; C D Storgaard; H Juneja; J Lundbye‐Jensen; S P Magnusson; C Couppé

doi:10.1111/apha.14030

. 2023 Sep 21;239(2):e14030. doi: 10.1111/apha.14030

Hormonal, immune, and oxidative stress responses to blood flow‐restricted exercise

M H Hjortshoej ^1,^2,^3,^4,^✉, P Aagaard ⁵, C D Storgaard ^1,^2,⁶, H Juneja ⁴, J Lundbye‐Jensen ⁶, S P Magnusson ^1,^2,³, C Couppé ^1,^2,³

PMCID: PMC10909497 PMID: 37732509

Abstract

Introduction

Heavy‐load free‐flow resistance exercise (HL‐FFRE) is a widely used training modality. Recently, low‐load blood‐flow restricted resistance exercise (LL‐BFRRE) has gained attention in both athletic and clinical settings as an alternative when conventional HL‐FFRE is contraindicated or not tolerated. LL‐BFRRE has been shown to result in physiological adaptations in muscle and connective tissue that are comparable to those induced by HL‐FFRE. The underlying mechanisms remain unclear; however, evidence suggests that LL‐BFRRE involves elevated metabolic stress compared to conventional free‐flow resistance exercise (FFRE).

Aim

The aim was to evaluate the initial (<10 min post‐exercise), intermediate (10–20 min), and late (>30 min) hormonal, immune, and oxidative stress responses observed following acute sessions of LL‐BFRRE compared to FFRE in healthy adults.

Methods

A systematic literature search of randomized and non‐randomized studies was conducted in PubMed, Embase, Cochrane Central, CINAHL, and SPORTDiscus. The Cochrane Risk of Bias (RoB2, ROBINS‐1) and TESTEX were used to evaluate risk of bias and study quality. Data extractions were based on mean change within groups.

Results

A total of 12525 hits were identified, of which 29 articles were included. LL‐BFRRE demonstrated greater acute increases in growth hormone responses when compared to overall FFRE at intermediate (SMD 2.04; 95% CI 0.87, 3.22) and late (SMD 2.64; 95% CI 1.13, 4.16) post‐exercise phases. LL‐BFRRE also demonstrated greater increase in testosterone responses compared to late LL‐FFRE.

Conclusion

These results indicate that LL‐BFRRE can induce increased or similar hormone and immune responses compared to LL‐FFRE and HL‐FFRE along with attenuated oxidative stress responses compared to HL‐FFRE.

Keywords: blood flow restriction, exercise, hormone, immune, meta‐analysis, oxidative stress

1. INTRODUCTION

Resistance training (FFRE), including heavy‐load FFRE (HL‐FFRE), is the most common exercise modality used for improving maximal muscle strength and inducing muscle hypertrophy and connective tissue adaptation. ¹ , ² HL‐FFRE also provides an efficient means to improve and maintain health and functional performance throughout life, ³ while it can also improve athletic performance and facilitate musculoskeletal rehabilitation. ⁴ , ⁵ However, despite being a common exercise modality, HL‐FFRE may not be suitable for all people as it produces high forces on joints, muscles, and connective tissue. ⁶ , ⁷ The physiological adaptations involved in FFRE are numerous and include: improvements in the efferent neural drive to myofibers, ⁸ , ⁹ , ¹⁰ , ¹¹ increased recruitment of high‐threshold motor units, ¹² increased anatomical muscle cross‐sectional area (CSA) and myofiber size, increased pennation angles of muscle fibers ¹³ , ¹⁴ , ¹⁵ and increased tendon CSA and stiffness, ¹⁶ , ¹⁷ , ¹⁸ which are accompanied by elevated hormonal responses to acute HL‐FFRE, for example, elevated plasma levels of testosterone, insulin‐like growth factor‐1 (IGF‐1), and growth hormone (GH). ¹⁹ , ²⁰

During the last decade, low‐load blood flow‐restricted resistance exercise (LL‐BFRRE) has received increasing attention in musculoskeletal research and clinical practice. ²¹ , ²² LL‐BFRRE appears to be safe in controlled conditions ²³ , ²⁴ , ²⁵ and to have significant clinical benefits in different populations, including individuals with musculoskeletal injury where HL‐FFRE exercise may not always be feasible or tolerable (e.g., early post‐operative phase following anterior cruciate ligament reconstruction, anterior knee pain, and osteoarthrosis). ²⁶ Meta‐analysis studies have documented that LL‐BFRRE effectively induces muscle hypertrophy of similar magnitude to HL‐FFRE both in young ²⁷ , ²⁸ and old healthy adults. ²⁹ Furthermore, a recent meta‐analysis has shown that comparable gains in maximal muscle strength may be achieved with LL‐BFRRE versus HL‐FFRE. ²⁷ In contrast, a previous meta‐analysis pointed toward superior muscle strength gains favoring HL‐FFRE, ²⁸ suggesting that neural adaptations may be superior with this training modality. Also, similar changes in structural and mechanical tendon properties have been observed following LL‐BFRRE compared to HL‐FFRE. ³⁰ , ³¹ The adaptive mechanisms of LL‐BFRRE have been proposed to involve a hypoxic cellular milieu leading to high levels of metabolic stress, ³² , ³³ increased fiber type recruitment, ³⁴ , ³⁵ , ³⁶ , ³⁷ proliferation of myogenic satellite cells leading to increased numbers of myonuclei, ³⁸ , ³⁹ , ⁴⁰ angiogenesis, ³⁷ , ⁴¹ , ⁴² along with elevated acute hormonal, ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ immune, ⁴⁷ , ⁴⁸ , ⁴⁹ and oxidative stress responses. ⁵⁰ , ⁵¹ , ⁵²

While the mechanisms of hypertrophy and strength gains related to training‐induced elevations in endogenous hormone secretion remain a matter of controversy, ⁵³ , ⁵⁴ , ⁵⁵ it has been speculated that certain circulating and paracrine hormones, for example, testosterone and IGF‐1, may play a critical role in activating intracellular signaling pathways (Akt–mTOR‐P70^S6k) and regulating myofibrillar protein synthesis. Other hormones, for example, GH, have been suggested to play an important role in upregulating type I collagen synthesis, thereby contributing to strengthening the extracellular matrix and supporting training‐induced increases in tendon CSA. ⁴⁶ , ⁵⁶ Other important factors that affect the magnitude of training‐induced muscle strength gains and hypertrophy comprise cytokines, such as interleukin‐6 (IL‐6), that are known to play an essential role in the muscle inflammatory responses and regeneration processes that may take place following acute bouts of high‐intensity physical activity, including LL‐BFRRE. ⁵⁷ , ⁵⁸ Likewise, oxidative stress responses in skeletal muscle, for example, reactive oxygen species (ROS) and nitric oxide (NO) formation, can have both beneficial and deleterious effects on muscle mass homeostasis depending on concentrations and exposure time ⁵⁹ , ⁶⁰ . and seem to play an essential role in muscle contraction, muscle fatigue, and oxidative damage and repair while also contributing to increase in the activity of enzymatic antioxidants. ⁵⁰ , ⁶⁰ , ⁶¹

Numerous studies have investigated the acute hormonal, immune, and oxidative stress responses elicited by LL‐BFRRE versus FFRE. However, to our best knowledge, no systematic literature review or meta‐analysis has previously synthesized the available evidence in this area. Thus, the aim of the present systematic review and meta‐analysis was to evaluate the initial (<10 min post‐exercise), intermediate (10–20 min post‐exercise), and late (30+ min post‐exercise) hormonal, immune, and oxidative stress responses following acute bouts of LL‐BFRRE compared to conventional heavy‐load (HL) and low‐load (LL) free‐flow resistance exercise (FFRE) in healthy human adults.

2. MATERIALS AND METHODS

2.1. Study design and registration

This systematic review and meta‐analysis followed the reporting guidelines of the preferred reporting items for systematic reviews and meta‐analysis (PRISMA), ⁶² and conformed to the good publishing practice in physiology. ⁶³ The protocol was registered (CRD42021276798) at the International Prospective Register of Systematic Reviews (PROSPERO) prior to the literature search, data extraction, and meta‐analysis.

2.2. Eligibility criteria

2.2.1. Population

This review included studies conducted in healthy trained and untrained male and female participants between 18 and 55 years of age and with an average body mass index (BMI) between 18.5 and 30 kg/m². Studies conducted in pediatric populations, and in patients who reported any disease, operative treatments, or with known diagnoses were excluded.

2.2.2. Acute exercise protocols

This review included studies that investigated BFRRE using low‐load (20%–40% of 1 repetition maximum (1RM)) exercise loads (LL‐BFRRE) versus conventional free‐flow resistance training using low (20–50% of 1‐RM) (LL‐FFRE) or heavy (≥70% of 1RM) (HL‐FFRE) exercise loads. No exclusion criteria were made regarding the magnitude of relative or absolute artery occlusion pressure (AOP) in LL‐BFRRE. In studies employing multiple AOPs, data obtained using the highest AOP were included. Studies using LL‐BFRRE in combination with other types of intervention, for example, electrical stimulation, vibration training, high‐altitude training, endurance training, and sprint training, were excluded.

2.2.3. Outcome variables

Studies that reported descriptive group mean data on acute hormonal, immune, or oxidative stress responses obtained following a single, acute bout of LL‐BFRRE compared to conventional FFRE (LL‐FFRE or HL‐FFRE) were included. Measurements should comprise either muscle biopsy sampling or the drawing of blood and/or saliva samples. Data were classified as initial (<10 min post‐exercise), intermediate (10–20 min post‐exercise), or late (30+ min post‐exercise) phase responses.

2.2.4. Study designs

Randomized and non‐randomized controlled and crossover trials were included in the present analysis. Studies without a control group that was performing conventional FFRE were excluded. Furthermore, literature reviews and single case studies were excluded. Specific inclusion and exclusion criteria are listed in Table 1.

TABLE 1.

Inclusion and exclusion criteria.

	Inclusion	Exclusion
Population	Healthy trained and untrained adults >18 to <55 years of age BMI >18.5 to <30	Middle‐aged >55 years of age Populations with any cardiovascular, metabolic, musculoskeletal diagnosis, any history of operative treatment, and animal studies
Intervention	Low‐Load Blood flow‐restricted resistance training (LL‐BFRRE)	All other interventions
Comparator	Conventional heavy‐load free flow resistance training (HL‐FFRE) or low‐load free flow resistance exercise (LL‐FFRE)	Other training interventions, for example, vibration and electrical stimulation
Outcome	Hormonal, immune, and oxidative stress responses measured by blood or saliva sampling, and/or muscle biopsy sampling at the initial (<10 min post‐exercise), intermediate (10–20 min post‐exercise), and late (30+ min post‐exercise) phases	Outcome of interest not reported
Study design	Randomized controlled trials, randomized crossover trials, non‐randomized controlled trials, and non‐randomized crossover trials	No comparator/control group

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Note : Table of inclusion and exclusion criteria for studies included in this systematic review and meta‐analysis.

2.3. Search methods and information sources

A comprehensive and systematic literature search for randomized and non‐randomized controlled and crossover studies was performed in Medline (via PubMed), Embase (via Ovid), Cochrane Central Register of Controlled Trials, CINAHL (via EBSCO), and SPORTDiscus (via EBSCO) with the latest update performed in March 2023. Three distinct search strategies were used to locate articles investigating the effect of LL‐BFRRE compared to FFRE on hormones, and immune and oxidative stress responses. Terms were searched in each database's medical subject heading (MeSH) and the Title/abstract, alternatively using the Abstract function. The search strategy was developed by MHH and CDS in consultation with senior co‐authors JLJ, HJ, PAa, SPM, and CC. The specific search strings were modified to accommodate each database. The specific search strategies for each database are listed in Supplementary Data—Search terms. Lastly, a cascade search of references listed in the included studies was performed. Results from all searches were combined and screened according to the inclusion and exclusion criteria presented in Table 1.

2.4. Study records

The search results derived from each database were extracted into Mendeley Citation Manager version 1.19.4, and duplicates were removed using semi‐automated tools. Two independent researchers (MHH, CDS) screened all titles and abstracts to identify articles eligible for full‐text reading. All eligible studies were assessed for predetermined selection and exclusion criteria, with reasons for exclusion noted in an Excel spreadsheet (Microsoft Corporation, Redmond, Washington). Disagreements were resolved by consensus wherever possible, and if necessary, by group discussions with PAa and CC. Specific inclusion and exclusion procedures are summarized in the PRISMA flow diagram (Figure 1).

Preferred reporting items for systematic reviews and meta‐analysis (PRISMA) flow chart that presents the number of studies involved at each step of the search and screening process with reasons for exclusion.

2.5. Data extraction

A standardized data extraction form was established in Excel (Microsoft Corporation, Redmond, Washington) and the following data were extracted from all included studies: author, year of publication, participants' characteristics (age, BMI, height, trained/untrained (hours per week), sex, number of included participants, and number of dropouts), exercise protocol (sets, repetitions, load intensity, AOP, volume, sessions per week, and number and types of exercise), and main outcome variables (hormonal, immune, and oxidative stress responses, timepoints, blood/saliva sample data, and muscle biopsy data if obtained). All data were extracted by the same investigator (MHH). If available, data for within‐group change scores (mean_change and SD_change) were collected. In case of incomplete data, the authors of the included studies were contacted by email. If corresponding authors were unable to retrieve data or did not respond, mean differences and pooled SD were estimated. In the case of only graphical reports (figures and graphs), WebPlotDigitizer (version 4.4, Pacifica, California, USA) was used to estimate data.

2.6. Assessment of study quality and risk of bias

Included studies were evaluated using the “Tool for the assessment of study quality and reporting in exercise” (TESTEX), ⁶⁴ which is a tool used for assessing study quality in training intervention studies. Secondly, risk of bias was assessed using the “Cochrane Collaboration tool to assess risk of bias” (ROB2 and ROBINS‐1) for randomized and non‐randomized studies, respectively. ⁶⁵ , ⁶⁶ , ⁶⁷ Studies were carefully reviewed and marked as “Low risk of bias” if randomization methods, participant allocation, blinding, and statistical analysis were performed satisfactorily. Studies were characterized as “High risk of bias” if they lacked a full description of randomization methods, participants allocation, blinding, or statistical analysis. Two independent reviewers (MHH, CDS) assessed study quality and risk of bias. In the case of disagreements not resolved by consensus, a third independent reviewer was consulted (CC). Funnel plots were visually inspected to evaluate publication bias.

2.7. Data analysis

The meta‐analysis was performed based on mean and standard deviation (SD) change scores from baseline to the initial (<10 min), intermediate (10–20 min), and late (30+ min) acute post‐exercise responses with LL‐BFRRE and FFRE. Mean_change and SD_change change scores were estimated from data available in the study or provided by the authors. To estimate missing data for SD_change, a correlation coefficient of 0.8 was assumed for any SD_change imputations. A correlation coefficient of 0.8 has been proposed as a standard to compute SD. ⁶⁸ However, we also performed sensitivity analyses computing SD_change using a correlation coefficient of 0.6. To estimate SD_change, we applied the following formulae ⁶⁸ :

\begin{matrix} {SD}_{change} \\ = \sqrt{{SD}^{2}_{baseline} + {SD}^{2}_{final} - (2 \times correlation \times {SD}_{baseline} \times {SD}_{final}^{0}} \end{matrix}

The standardized mean difference (SMD) was calculated as an overall comparable estimate due to the differing methods of measuring hormone, immune, and oxidative stress responses by means of blood, saliva, and muscle biopsy sampling, respectively. A random‐effects model was used in the meta‐analysis, and outcomes are presented as SMD with a 95% confidence interval. SMD was computed based on Hedge's g, and a SMD of 0.2–0.5 was considered a small effect size, SMD of 0.5–0.8 was considered a moderate effect, and a SMD >0.8 was considered a large effect. ⁶⁸ To assess the degree of statistical heterogeneity between the included studies, I ² was calculated and interpreted as follows: I ² of 0%–40% might not be important, 30%–60% may represent moderate heterogeneity, 50%–90% may represent substantial heterogeneity, and 75%–100% is considerable heterogeneity. ⁶⁸ All statistical analyses were performed using the software Review manager (RevMan, version 5.4.1) provided by the Cochrane Collaboration.

2.8. Subgroup analysis

Subgroup analysis was performed on study design where only randomized controlled trials and randomized crossover trials were analyzed. In addition, a subgroup analysis based on loading intensity was performed comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE, respectively.

3. RESULTS

3.1. Study selection

A total of 12525 study records were identified. Of these, 4664 were identified as duplicates and were removed, thereby leaving 7861 hits to be assessed through screening of the title/abstract. Based hereon, 274 studies were examined for eligibility, of which 29 studies were included in the systematic review and meta‐analysis. Eight studies were randomized controlled trials, twelve were randomized cross‐over trials, one was a non‐randomized trial, and eight were non‐randomized cross‐over trials. A schematic representation of the search and screening process is provided in Figure 1. The search results from each database are presented in Supplementary Data—Search history.

3.2. Included studies

An overview of study demographics and training characteristics is provided in Tables 2 and 3, respectively. Twenty‐nine studies investigated the hormonal, immune, and/or oxidative stress responses following acute LL‐BFRRE compared to FFRE. The total sample population was n = 427 and included 362 male and 25 female participants, while 40 participants were not classified by sex. The mean age was 23.2 years (range 18.7–34.0), mean height was 175 cm (range 167–184), mean weight was 75.3 kg (range 62.3–86.21), and BMI averaged 24.3 kg/m² (range 21.0–29.0). The overall population consisted of primarily physically active adults (69% of the study population). The acute exercise protocols included: isotonic knee extension (17 studies), isotonic knee flexion (4 studies), leg press (4 studies), front squats (1 study), half squat (2 studies), calf extension (3 studies), bench press (4 studies), pull down (2 studies), shoulder press (1 study), biceps curls (11 studies), and triceps extension (2 studies). Biological samples comprised the withdrawal of blood (27 studies) and muscle biopsies (3 studies); a single study collected both blood and muscle biopsy samples.

TABLE 2.

Study characteristics of included studies (demographic data).

Author	Year	Study Design	n		Dropouts		Sex		Age (years)		BMI (kg/m2)		Height (cm)		Weight (kg)
Author	Year	Study Design	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE
Bemben et al. A	2022	Randomized controlled trial	12	12	No drop‐outs	No drop‐outs	12 males	12 males	21.30 ± 2.50	20.90 ± 2.90	25.90 ^a	25.60*	179.70 ± 4.40	179.90 ± 7.50	83.50 ± 17.80	82.80 ± 24.40
Bemben et al. B	2022	Randomized controlled trial	12	9	No drop‐outs	No drop‐outs	12 males	9 males	21.30 ± 2.50	20.60 ± 1.70	25.90 ^a	22.70 ^a	179.70 ± 4.40	176.70 ± 5.70	83.50 ± 17.80	71.00 ± 7.80
Boeno et al. A	2018	Randomized crossover trial	11	11	No drop‐outs	No drop‐outs	11 males	11 males	23.72 ± 3.49	23.72 ± 3.49	Not reported	Not reported	Not reported	Not reported	81.55 ± 6.10	81.55 ± 6.10
Boeno et al. B	2018	Randomized crossover trial	11	11	No drop‐outs	No drop‐outs	11 males	11 males	23.72 ± 3.49	23.72 ± 3.49	Not reported	Not reported	Not reported	Not reported	81.55 ± 6.10	81.55 ± 6.10
Bugera et al. A	2018	Randomized crossover trial	9	9	1 participant dropped out due to adverse reaction to blood drawing procedure	1 participant dropped out due to adverse reaction to blood drawing procedure	10 males	10 males	25.78 ± 3.56	25.78 ± 3.56	25.93 ± 2.22	25.93 ± 2.22	175.00 ± 7.00	175.00 ± 7.00	79.74 ± 8.82	79.74 ± 8.82
Bugera et al. B	2018	Randomized crossover trial	9	9	1 participant dropped out due to adverse reaction to blood drawing procedure	1 participant dropped out due to adverse reaction to blood drawing procedure	10 males	10 males	25.78 ± 3.56	25.78 ± 3.56	25.93 ± 2.22	25.93 ± 2.22	175.00 ± 7.00	175.00 ± 7.00	79.74 ± 8.82	79.74 ± 8.82
Centner et al. A	2018	Counterbalanced crossover trial	15	15	No drop‐outs	No drop‐outs	15 males	15 males	24.80 ± 2.60	24.80 ± 2.60	24.00 ± 2.50	24.00 ± 2.50	178.60 ± 6.90	178.60 ± 6.90	76.50 ± 7.40	76.50 ± 7.40
Centner et al. B	2018	Counterbalanced crossover trial	15	15	No drop‐outs	No drop‐outs	15 males	15 males	24.80 ± 2.60	24.80 ± 2.60	24.00 ± 2.50	24.00 ± 2.50	178.60 ± 6.90	178.60 ± 6.90	76.50 ± 7.40	76.50 ± 7.40
Drummond et al.	2008	Randomized crossover trial	6	6	No drop‐outs	No drop‐outs	6 males	6 males	32 ± 4.90	32 ± 4.90	29 ± 2.45	29 ± 2.45	170 ± 5.00	170 ± 5.00	84 ± 9.80	84 ± 9.80
Ellefsen et al.	2015	Randomized crossover trial	7	7	8 (3 dropped out during study; 3 participants refrained from biopsies and blood samples; and 2 participants were unable to perform blood tests and therefore not included in analysis)		7 females	7 females	23 ± 3	23 ± 3	25.10 ^a	25.10 ^a	167 ± 8.00	167 ± 8.00	70 ± 20	70 ± 20
Ferguson et al.	2018	Counterbalanced non‐randomized crossover trial	6	6	No drop‐outs	No drop‐outs	6 males	6 males	26 ± 2	26 ± 2	24.50	24.50	184 ± 6	184 ± 6	83 ± 11	83 ± 11
Fujita et al.	2007	Randomized crossover trial	6	6	No drop‐outs	No drop‐outs	6 males	6 males	32 ± 4.90	32 ± 4.90	29 ± 2.45	29 ± 2.45	170 ± 5.00	170 ± 5.00	84 ± 9.80	84 ± 9.80
Garten et al. A	2015	Counterbalanced Crossover trial	12	12	No drop‐outs	No drop‐outs	15 males	15 males	25 ± 3	25 ± 3	25 ± 2	25 ± 2	179 ± 6	179 ± 6	80 ± 7	80 ± 7
Garten et al. B	2015	Counterbalanced Crossover trial	12	12	No drop‐outs	No drop‐outs	15 males	15 males	25 ± 3	25 ± 3	25 ± 2	25 ± 2	179 ± 6	179 ± 6	80 ± 7	80 ± 7
Goldfarb et al.	2008	Counterbalanced Crossover trial	7	7	No drop‐outs	No drop‐outs	7 males	7 males	21.30 ± 12.70	21.30 ± 12.70	26.40 ^a	26.40 ^a	180.53 ± 15.27	180.53 ± 15.27	86.21 ± 18.20	86.21 ± 18.20
Hughes et al.	2020	Randomized crossover trial	12	12	No drop‐outs	No drop‐outs	10 males; 2 females	10 males; 2 females	29 ± 6	29 ± 6	26.07 ± 3.29	26.07 ± 3.29	178 ± 8.00	178 ± 8.00	81.10 ± 10.70	81.10 ± 10.70
Kim et al.	2014	Randomized crossover trial	13	13	No drop‐outs	No drop‐outs	13 females	13 females	21.50 ± 2.13	21.50 ± 2.13	Not reported	Not reported	168 ± 7.21	168 ± 7.21	Not reported	Not reported
Kraemer et al.	2016	Counterbalanced Crossover trial	8	8	No drop‐outs	No drop‐outs	8 males	8 males	21.80 ± 1.40	21.80 ± 1.40	26.70 ^a	26.70 ^a	179.20 ± 6.50	179.20 ± 6.50	85.90 ± 6.50	85.90 ± 6.50
Larkin et al.	2012	Randomized crossover trial	6	6	No drop‐outs	No drop‐outs	3 males; 3 females	3 males; 3 females	22.00 ± 2.45	22.00 ± 2.45	23.70 ± 3.43	23.70 ± 3.43	Not reported	Not reported	72 ± 17.15	72 ± 17.15
Laurentino et al. A	2022	Randomized controlled trial	10	10	No drop‐outs	No drop‐outs	10 males	10 males	20.00 ± 4.50	20.30 ± 4.20	23.50 ^a	24.40 ^a	175.20 ± 9.00	175.70 ± 4.90	72.10 ± 11.90	75.30 ± 15.40
Laurentino et al. B	2022	Randomized controlled trial	10	9	No drop‐outs	No drop‐outs	10 males	9 males	20.00 ± 4.50	23.60 ± 6	23.50 ^a	24.50 ^a	175.20 ± 9.00	173.60 ± 6.00	72.10 ± 11.90	73.80 ± 12.00
Lima et al.	2021	Randomized controlled trial	9	9	No drop‐outs	No drop‐outs	9 males	9 males	23.30 ± 2.00	22.00 ± 1.90	22.80 ± 2.70	22.30 ± 2.70	Not reported	Not reported	Not reported	Not reported
Madarame et al.	2008	Randomized controlled trial	5	5	Originally 8 and 7 participants were recruited but they performed a substudy on 5 participants in each group		5 males	5 males	25.80 ± 3.20	25.80 ± 3.20	26.40 ^a	25.50 ^a	177.00 ± 3.90	173.60 ± 4.60	82.60 ± 18.40	72.70 ± 6.30
Manini et al.	2012	Randomized crossover trial	10	10	No drop‐outs	No drop‐outs	10 males	10 males	28 ± 7.80	28 ± 7.80	25.90 ± 2.80	25.90 ± 2.80	173.70 ± 7.30	173.70 ± 7.30	78.10 ± 7.60	78.10 ± 7.60
Neto et al. A	2018	Randomized crossover trial	10	10	No drop‐outs	No drop‐outs	10 males	10 males	19 ± 0.80	19 ± 0.80	25.70 ± 2.70	25.70 ± 2.70	174.60 ± 5.40	174.60 ± 5.40	78.80 ± 10.80	78.80 ± 10.80
Neto et al. B	2018	Randomized crossover trial	10	10	No drop‐outs	No drop‐outs	10 males	10 males	19 ± 0.80	19 ± 0.80	25.70 ± 2.70	25.70 ± 2.70	174.60 ± 5.40	174.60 ± 5.40	78.80 ± 10.80	78.80 ± 10.80
Ozaki et al.	2013	Randomized Controlled trial	7	7	The original study investigated 10 in the BFRRE group and 9 in the HL‐FFRE group. They did not report why only 14 participants underwent blood sampling		7 males	7 males	23 ± 0	24 ± 2,65	21.70 ± 2.12	21.40 ± 2.12	172.00 ± 5.29	171.00 ± 2.65	63.90 ± 6.35	62.30 ± 7.67
Ramis et al.	2020	Randomized Controlled trial	15	13	No drop‐outs	2 drop‐outs due to personal reasons	15 males	13 males	23.52 ± 2.77	24.46 ± 2.56	25.50 ^a	25.90 ^a	173.00 ± 6.00	175.00 ± 5.00	76.26 ± 12.76	79.36 ± 11.30
Reeves et al.	2006	Randomized crossover trial	8	8	No drop‐outs	No drop‐outs	8 males	8 males	21.80 ± 1.40	21.80 ± 1.40	26.70	26.70	179.20 ± 6.50	179.20 ± 6.50	85.90 ± 6.50	85.90 ± 6.50
Sharifi et al. A	2020	Randomized controlled trial	8	8	No drop‐outs	No drop‐outs	Not reported	Not reported	21.25 ± 1.90	18.75 ± 1.46	23.30 ± 3.71	22.00 ± 1.88	173 ± 4.11	177 ± 5.59	70.0 ± 4.55	69 ± 5.31
Sharifi et al. B	2020	Randomized controlled trial	8	8	No drop‐outs	No drop‐outs	Not reported	Not reported	18.75 ± 1.63	20.12 ± 2.19	22.40 ± 2.26	21.50 ± 1.32	174 ± 5.78	177 ± 4.53	68 ± 4.23	75 ± 5.42
Takano et al.	2005	Non‐randomized crossover trial	9	9	2 drop‐outs	2 drop‐outs	9 males	9 males	34 ± 6	34 ± 6	22.10 ± 2.50	22.10 ± 2.50	175.80 ± 6.90	175.80 ± 6.90	68.10 ± 7.80	68.10 ± 7.80
Takarada et al.	2004	Non‐randomized controlled trial	6	6	No drop‐outs	No drop‐outs	6 males	6 males	21.30 ± 0.60	21.80 ± 0.80	23.60 ^a	24.10 ^a	171.40 ± 2.90	173.40 ± 3.20	69.30 ± 5.20	72.40 ± 6.80
Takarada et al.	2000	Non‐randomized crossover trial	6	6	No drop‐outs	No drop‐outs	6 males	6 males	20–22 years of age	20–22 years of age	26.30 ^a	26.30 ^a	173.80 ± 6.70	173.80 ± 6.70	79.40 ± 8.70	79.40 ± 8.70
Vilaça‐Alves	2022	Randomized crossover trial	10	10	No drop‐outs	No drop‐outs	10 males	10 males	22.50 ± 3.24	22.50 ± 3.24	23.00	23.00	177.30 ± 4.76	177.30 ± 4.76	72.20 ± 8.06	72.20 ± 8.06
Yinghao et al.	2021	Randomized crossover trial	25	25	No drop‐outs	No drop‐outs	25 males	25 males	19.80 ± 2.20	19.80 ± 2.20	21.80 ± 0.80	21.80 ± 0.80	176.70 ± 5.20	176.70 ± 5.20	67.50 ± 2.60	67.50 ± 2.60
Zhao et al.	2020	Randomized controlled trial	8	8	No drop‐outs	No drop‐outs	8 males	8 males	19 ± 1	19 ± 1	21.01 ± 4.97	21.54 ± 3.15	175.7 ± 5.20	175.2 ± 3.92	67.0 ± 10.7	68.2 ± 12.3

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Note: Table of demographic data presented in mean and standard deviation.

^{^a}

Indicates BMI has been calculated based on mean weight and height as it was not reported in the study 95% confidence interval (95%CI).

TABLE 3.

Study characteristics (Training data).

Author

Training status

Types of exercises

1‐RM (kg)

Sets & repetitions

Load intensity (% of 1‐RM)

Volume (load (kg) × repetitions)

LL‐BFRRE

FFRE

LL‐BFRRE

FFRE

LL‐BFRRE

FFRE

LL‐BFRRE

FFRE

LL‐BFRRE

FFRE

LL‐BFRRE

FFRE

Bemben et al. A

Physically active healthy individuals

4 upper body exercises without occlusion (lat pull down, shoulder press, biceps curls, and triceps extension) and 2 lower limb exercises with occlusion (knee extension and knee flexion)

Knee extension 1‐RM: 90.30 ± 17.70. Knee flexion 1‐RM: 87.00 ± 20.30

Knee extension 1‐RM: 99.00 ± 16.90. Knee flexion 1‐RM: 96.70 ± 16.70

30, 15, 15, 15

10, 10, 10

20% of 1‐RM

70% of 1‐RM

Not reported

Bemben et al. B

Physically active healthy individuals

4 upper body exercises without occlusion (lat pull down, shoulder press, biceps curls, and triceps extension) and 2 lower limb exercises with occlusion (knee extension and knee flexion)

Knee extension 1‐RM: 90.30 ± 17.70. Knee flexion 1‐RM: 87.00 ± 20.30

Knee extension 1‐RM: 88.1 ± 14.8. Knee flexion 1‐RM: 85.60 ± 9.20

30, 15, 15, 15

15, 15, 15

20% of 1‐RM

45% of 1‐RM

Not reported

Boeno et al. A

Physically active healthy individuals

Leg press and bilateral elbow flexion

Leg press 1‐RM: 172.52 ± 29.20. Bilateral elbow flexion 1‐RM: 18.00 ± 3.19

4 sets until failure. Mean repetitions performed for leg press: 20.30 ± 6.30 and bilateral elbow flexion: 21.20 ± 5.

4 sets until failure. Mean repetitions performed for leg press: 22.00 ± 10.80 and bilateral elbow flexion: 5.70 ± 3

30% of 1‐RM

80% of 1‐RM

Not reported

Boeno et al. B

Physically active healthy individuals

Leg press and bilateral elbow flexion

Leg press 1‐RM: 172.52 ± 29.20. Bilateral elbow flexion 1‐RM: 18.00 ± 3.19

4 sets until failure. Mean repetitions performed for leg press: 20.30 ± 6.30 and bilateral elbow flexion: 21.20 ± 5.30

4 sets until failure. Mean repetitions performed for leg press: 89.40 ± 23.30 and bilateral elbow flexion: 28.40 ± 23.30

30% of 1‐RM

Not reported

Bugera et al. A

Trained individuals with at least 1‐year experience with resistance exercise

Bilateral knee extension

Bilateral knee extension 1‐RM: 115.40 ± 21.50

30, 15, 15, 15

7, 7, 7, 7

30% of 1‐RM

80% of 1‐RM

Not reported but stated to be approximately equal by authors

Bugera et al. B

Trained individuals with at least 1‐year experience with resistance exercise

Trained with at least 1‐year experience with RE

Bilateral knee extension

Bilateral knee extension 1‐RM: 115.40 ± 21.50

30, 15, 15, 15

30% of 1‐RM

Not reported but stated to be approximately equal by authors

Centner et al. A

At least 1 year experience with resistance exercise (average experience in years: 5.8 ± 3.4)

Front squats

Not reported

30, 15, 15, 15. All repetitions were completed

10, 10, 10 (average repetition completed pr set: Set 1: 10 ± 0, Set 2: 9 ± 1, Set 3: 8 ± 2)

30% of 1‐RM

80% of 1‐RM

Not reported

Centner et al. B

At least 1 year experience with resistance exercise (average experience in years: 5.8 ± 3.4)

Front squats

Not reported

30, 15, 15, 15. All repetitions were completed

30% of 1‐RM

Not reported

Drummond et al.

Physically active but not engaged in resistance exercise

Bilateral knee extension

Not reported

30, 15, 15, 15

20% of 1‐RM

Not reported

Ellefsen et al.

Untrained individuals

Unilateral knee extension

Unilateral knee extension 1‐RM: 38.87 ± 7.03

Unilateral knee extension 1‐RM: 39,13 ± 7.14

5 sets of repetitions to failure. Average repetition pr. training session in week 1: 76 ± 19

3 sets of 30 ± 0 first session.

30% of 1‐RM

74–81% of 1‐RM

934 ± 275 (weekly training volume)

813 ± 138 (weekly training volume)

Ferguson et al.

Physically trained individuals but none were specifically used to resistance exercise

Bilateral knee extension

Bilateral knee extension 1‐RM: 141 ± 21

30, 15, 15, and until failure with average repetitions: 37 ± 28. Total repetitions were 97 ± 28

20% of 1‐RM = average of 28 ± 4 kg.

Not reported

Fujita et al.

Physically trained individuals but none were specifically used to resistance exercise

Bilateral knee extension

Not reported

30, 15, 15, 15

20% of 1‐RM

Not reported

Garten et al. A

Participants had experience with resistance exercise

Unilateral elbow flexion

Unilateral elbow flexion 1‐RM: 19.89 ± 3.23

3 sets until failure. Mean repetitions performed 53.50 ± 13.80

3 sets until failure. Mean repetitions performed 18.60 ± 4.90

30% of 1‐RM

Not reported

Garten et al. B

Participants had experience with resistance exercise

Unilateral elbow flexion

1‐RM: 19.89 ± 3.23

Unilateral elbow flexion

1‐RM: 19.89 ± 3.23

3 sets until failure. Mean repetitions performed 53.5 ± 13.80

3 sets until failure. Mean repetitions performed 77.25 ± 22.40

30% of 1‐RM

70% of 1‐RM

Not reported

Goldfarb et al.

Participants had experience with resistance exercise

Unilateral bicep curls and calf extension

Not reported

3 sets

until failure

3 sets

until failure

30% of 1‐RM

70% of 1‐RM

Not reported

Hughes et al.

Physically active healthy individuals

Unilateral leg press

Unilateral LEG press

Unilateral Leg press 1‐RM: 156 ± 52

30, 15, 15, 15

10,10,10,10

30% of 1‐RM

70% of 1‐RM

3211 ± 1206

4375 ± 1454

Kim et al.

Physically active healthy individuals

Isotonic knee extension and leg press.

Knee extension 1‐RM: 67.90 ± 15.14. Leg press 1‐RM: 99.40 ± 21.63

30, 15, 15

10,10,10

20% of 1‐RM

80% of 1‐RM

Approx. 2008

Approx. 4017

Kraemer et al.

Not reported

Unilateral bicep curls and unilateral calf extension.

Unilateral bicep curls 1‐RM: 23.30 ± 2.50. Unilateral calf extension 1‐RM: 130.70 ± 16.10

3 sets until failure

30% of 1‐RM. Mean intensity for bicep curls: 7.40 ± 1.10 kg and mean 1‐RM calf extension: 39.50 ± 5.10 kg

70% of 1‐RM. Mean intensity for bicep curls: 16.20 ± 2.30 kg and mean 1‐RM calf extension: 91.80 ± 10.50

Not reported

Larkin et al.

Non‐regular exercisers

Unilateral leg extension.

Unilateral leg extension 1‐RM: 44 ± 17.15

10 sets of 12 repetitions.

40% of 1‐RM

Not reported

Laurentino et al. A

Physically active healthy individuals

Bilateral knee extension

Bilateral knee extension 1‐RM: 84.70 ± 14.50

Bilateral knee extension 1‐RM: 86.20 ± 9.50

4 sets of 15 repetitions

20% of 1‐RM

Not reported

Laurentino et al. B

Physically active healthy individuals

Bilateral knee extension

Bilateral knee extension 1‐RM: 84.70 ± 14.50

Bilateral knee extension 1‐RM: 86.90 ± 15.20

4 sets of 15 repetitions

4 sets of 8–10 repetitions

20% of 1‐RM

80% of 1‐RM

Not reported

Lima et al.

Physically active healthy individuals

Barbell arm curl

Barbell arm curl 1‐RM: 54.67 ± 5.51

Barbell arm curl 1‐RM: 47.16 ± 7.51

6 sets until failure

20% of 1‐RM

75% of 1‐RM

1558.33 ± 462.50

1016.67 ± 483.33

Madarame et al. ⁷³

Untrained individuals

Bilateral knee extension and knee flexion

Not reported

30, 15, 15

30% of 1‐RM

Not reported

Manini et al.

Untrained individuals

Bilateral knee extension

Bilateral knee extension 1‐RM: 115 ± 19.60

4 sets until failure. Average repetitions performed was 110.3 ± 8.6

4 sets until failure. Average repetitions performed was 46.1 ± 2.1

20% of 1‐RM

80% of 1‐RM

2519 ± 208.00

4283 ± 312.00

Neto et al. A

Recreationally trained participants (experience with resistance training ranged from 1 to 5 years)

Bilateral bench press, front pulldown, triceps curl, biceps curl

Not reported

30, 15, 15, 15

8, 8, 8

20% of 1‐RM

80% of 1‐RM

4131.00 ± 608.20

5598.70 ± 836.70

Neto et al. B

Recreationally trained participants (experience with resistance exercise ranged from 1 to 5 years)

Bilateral bench press, front pulldown, triceps curl, biceps curl

Not reported

30, 15, 15, 15

8, 8, 8

20% of 1‐RM

80% of 1‐RM

4131.00 ± 608.20

5598.70 ± 836.70

Ozaki et al.

Physically active healthy individuals

Flat bench press

Flat bench press 1‐RM: 49.30 ± 2.60

Flat bench press 1‐RM: 47.50 ± 3.40

30, 15, 15, 15

10, 10, 10

30% of 1‐RM

75% of 1‐RM

Training volume similar between groups reported by authors

Ramis et al.

Physically active healthy individuals

Unilateral elbow flexion and unilateral knee extension

Not reported

4 sets and repetitions were calculated to ensure equal volume between groups. For elbow flexion, 21 repetition pr set and 23 for knee extension

8, 8, 8, 8

30% of 1‐RM. Unilateral elbow flexion mean intensity: 4.78 ± 1.01. Unilateral knee extension mean intensity: 21.82 ± 5.2

80% of 1‐RM. Unilateral elbow flexion mean intensity: 12.36 ± 2.42. Unilateral knee extension mean intensity: 64.49 ± 11.78

Training volumes were matched to heavy FFRE for elbow flexion: 395.21 and for knee extension: 2065.75

Training volume for elbow flexion: 395.21 and for knee extension: 2065.75

Reeves et al.

Trained individuals

Single‐arm bicep curl and single‐leg calf extension

Biceps curls 1‐RM: 23.30 ± 2.50. Calf extension 1‐RM: 130.70 ± 16.10

3 sets until failure. Biceps curls average repetitions Set 1: 23 ± 2.50, set 2: 9.60 ± 1.90, set 3: 7.80 ± 2.50. Calf extension average repetitions Set 1: 29.60 ± 9.30, set 2: 16.60 ± 4.20, set 3: 14.80 ± 2.30

3 sets until failure. Biceps curls average repetitions Set 1: 10.20 ± 1.90, set 2: 5.40 ± 1.10, set 3: 4.20 ± 1.40. Calf extension average repetitions Set 1: 14.00 ± 1.40, set 2: 11.30 ± 3.70, set 3: 9.10 ± 1.40

30% of 1‐RM. Average bicep curls 30% of 1‐RM: 7.40 ± 1.10. Average calf extension 30% of 1‐RM: 39.50 ± 5.10

70% of 1‐RM. Average bicep curls 70% of 1‐RM: 16.20 ± 2.30. Average calf extension 70% of 1‐RM: 91.80 ± 10.50

Not reported

Sharifi et al. A

Untrained individuals

Leg press, leg hug, leg extension, chest press, barbell biceps curl, and dumbbells biceps curls

Leg press 1‐RM: 185 ± 20.11. Barbell chest press 1‐RM: 57 ± 7.52

Leg press 1‐RM: 195 ± 19.11. Barbell chest press 1‐RM: 69 ± 7.88

20, 20, 20

10,10,10

20% of 1‐RM

70% of 1‐RM

Not reported

Sharifi et al. B

Untrained individuals

Leg press, leg hug, leg extension, chest press, barbell biceps curl, and dumbbells biceps curls

Leg press 1‐RM: 170 ± 14.82. Barbell chest press 1‐RM: 68 ± 7.44

Leg press 1‐RM: 175 ± 17.01. Barbell chest press 1‐RM: 59 ± 6.45

20, 20, 20

10,10,10

20% of 1‐RM

70% of 1‐RM

Not reported

Takano et al.

Untrained individuals

Bilateral knee extension

Not reported

1 set of 30 repetitions following 3 sets to failure

20% of 1‐RM

Not reported

Takarada et al.

Untrained individuals

Bilateral isotonic knee extension

Not reported

5 sets performed until failure with a mean of 18.20 ± 1.47 repetitions pr set. Mean repetition pr set for Set 1: 23.30 ± 2.69, Set 2: 18.4 ± 1.96, Set 3: 17.20 ± 1.45, Set 4: 16.30 ± 1.71, Set 5: 15.20 ± 2.45

Repetitions were matched to BFRRE

≈ 20% of 1‐RM with a mean of 17.6 ± 4.90% of 1‐RM. Mean % of 1‐RM for Set 1: 21.60 ± 6.61, Set 2: 20.20 ± 5.88, Set 3: 18.80 ± 7.10, Set 4: 16.30 ± 6.12 Set 5: 16.4 ± 6.37

≈ 20% of 1‐RM. Intensity was matched to BFRRE

Not reported but stated to be equal by authors

Takarada et al.

Athletes

Bilateral isotonic knee extension

Not reported

5 sets were performed until failure with a mean of 14.4 ± 3.92 repetitions pr set. Mean repetition pr set for set 1: 20.00 ± 4.41, Set 2: 12.20 ± 4.16, Set 3: 11.30 ± 3.67, Set 4: 15.20 ± 2.69, Set 5: 13.2 ± 2.69

Repetitions were matched to BFRRE

≈ 20% of 1‐RM with a mean of 23.2 ± 12.74% of 1‐RM. Mean % of 1‐RM for set 1: 33.20 ± 3.92, set 2: 28.20 ± 5.14, Set 3: 20.90 ± 1.71, Set 4: 18.00 ± 4.65 Set 5: 15.50 ± 4.90

≈ 20% of 1‐RM. Intensity was matched to BFRRE

Not reported

Vilaça‐Alves

Individuals with experience in resistance exercise (3 times pr. week for 6 months)

Half squat and bench press

Half squat 1‐RM: 108.00 ± 28.98. Bench press 1‐RM: 61.50 ± 18.27

30, 15, 15, 15

8,8,8 + 20 repetitions at 40% of 1‐RM.

20% of 1‐RM

75% of 1‐RM

2542.50 ± 687.80

4731.00 ± 1271.76

Yinghao et al.

Physically inactive individuals

Knee flexion and knee extension

1‐RM: 86.8 ± 8.8. It is not reported which exercise 1‐RM is measured and there is only reported one 1‐RM

15, 15, 15, 15, 15, 15

30% of 1‐RM with a mean of 26.0 ± 2.6

Not reported

Zhao et al.

Physically active healthy individuals

Bicep curls

11.88 ± 1.90

12.81 ± 1.46

20, 20, 20, 20, 20

30% of 1‐RM

Not reported

Author	AOP		Rest between sets		Training sessions		Outcome	Timepoints	Methodology for measuring outcome
Author	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE	LL‐BFRRE	FFRE	Outcome	Timepoints	Methodology for measuring outcome
Bemben et al. A	5‐cm wide cuffs with an absolute training pressure of 160 mmHg in a continuous fashion	NA	1 min	1 min	3 training sessions pr week for 6 weeks	3 training sessions pr week for 6 weeks	Testosterone, cortisol, and insulin‐like growth factor‐1	Initial post‐exercise	Blood sample
Bemben et al. B	5‐cm wide cuffs with an absolute training pressure of 160 mmHg in a continuous fashion	NA	1 min	1 min	3 training sessions pr week for 6 weeks	3 training sessions pr week for 6 weeks	Testosterone, cortisol, and insulin‐like growth factor‐1	Initial post‐exercise	Blood sample
Boeno et al. A	Cuffs were inflated to 20 mmHg below Systolic blood pressure (systolic blood pressure: not reported) for bilateral elbow flexion and 20 mmHg greater than systolic blood pressure	NA	1 min	1 min	Trial days were seperated by 72 h	Trial days were seperated by 72 h	Superoxide dismutase, catalase, and nitric oxide	Initial post‐exercise	Blood sample
Boeno et al. B	Cuffs were inflated to 20 mmHg below Systolic blood pressure (systolic blood pressure: not reported) for bilateral elbow flexion and 20 mmHg greater than systolic blood pressure	NA	1 min	1 min	Trial days were seperated by 72 h	Trial days were seperated by 72 h	Superoxide dismutase, catalase, and nitric oxide	Initial post‐exercise	Blood sample
Bugera et al. A	5‐cm wide KAATSU air‐bands were inflated to 200 mmHg in a continuous fashion	NA	30 s	1 min	One exercise condition pr. week	One exercise condition pr. week	Interleukin‐6, Interleukin‐15, and decorin	Initial post‐exercise	Blood sample
Bugera et al. B	5‐cm wide KAATSU air‐bands were inflated to 200 mmHg in a continuous fashion	NA	30 s	30 s	One exercise condition pr. week	One exercise condition pr. week	Interleukin‐6, Interleukin‐15, and decorin	Initial post‐exercise	Blood sample
Centner et al. A	20‐cm wide nylon pneumatic cuff was inflated to 50% of individual AOP (Average 100% AOP: 164.5 ± 9.7) in a continuous fashion	NA	30 s	2 min	Trial days were separated by at least 48 h	Trial days were separated by at least 48 h	Systemic total reactive oxygen species, and Local total reactive oxygen species	Initial post‐exercise	Blood sample
Centner et al. B	20‐cm wide nylon pneumatic cuff was inflated to 50% of individual AOP (Average 100% AOP: 164.5 ± 9.7) in a continuous fashion	NA	30 s	30 s	Trial days were separated by at least 48 h	Trial days were separated by at least 48 h	Systemic total reactive oxygen species, and Local total reactive oxygen species	Initial post‐exercise	Blood sample
Drummond et al.	5‐cm cuff inflated to an absolute measure of 200 mmHg	NA	30 s	30 s	Trial days were separated by 3 weeks	Trial days were separated by 3 weeks	Insulin‐like growth factor‐1 mRNA	Initial and 3 hours post‐exercise	Muscle Biopsy
Ellefsen et al.	18‐cm cuff inflated to an absolute measure of 90 mmHg	NA	45 s	90 s	2 sessions pr. week	2 sessions pr. week	Growth hormone, Cortisol, sex hormone binding globulin, and androstendione	Initial and 30 min post‐exercise	Blood sample
Ferguson et al.	13‐cm wide pneumatic cuffs were inflated to an absolute measure of 110 mmHg	NA	30 s	30 s	1 session of BFR and FFRE with 3 weeks between each session	1 session of BFR and FFRE with 3 weeks between each session	Vascular endothelial growth factor, and endothelial nitric oxide synthase	2 h post‐exercise	Mucle biopsy1
Fujita et al.	5‐cm cuff inflated to an absolute measure of 200 mmHg	NA	30 s	30 s	two separate occasion (not specified)	two separate occasion (not specified)	Growth hormone, cortisol, insulin‐like growth factor‐1, and total testosterone	Initial, 20, and 30 min post‐exercise	Blood sample
Garten et al. A	Cuffs were inflated to 20 mmHg below Systolic blood pressure (Mean systolic blood pressure:113 ± 13 mmHg) for unilateral elbow flexion in a continuous fashion	NA	1 min	1 min	Trial days were separated by at least 72 h	Trial days were separated by at least 72 h	Protein carbonyls, glutathione ratio	Initial post‐exercise	Blood sample
Garten et al. B	Cuffs were inflated to 20 mmHg below Systolic blood pressure (Mean systolic blood pressure:113 ± 13 mmHg) for unilateral elbow flexion in a continuous fashion	NA	1 min	1 min	Trial days were separated by at least 72 h	Trial days were separated by at least 72 h	Protein carbonyls, glutathione ratio	Initial post‐exercise	Blood sample
Goldfarb et al.	Cuff were inflated to 20 mmHg below systolic blood pressure (mean systolic blood pressure: Not reported) for bicep curls and 40 mmHg above bicep curls pressure in a continuous pressure	NA	1 min	1 min	Not reported	Not reported	Protein carbonyls, glutathione	Initial and 15 min post‐exercise	Blood sample
Hughes et al.	11.5‐cm cuff inflated to a relative measure 80% of AOP (average exercising pressure 158 ± 10)	NA	30 s	53 s	All experiment days were separated by at least 72 h	All experiment days were separated by at least 72 h	β‐endorphin and 2‐arachidonoylglycerol	5 min & 24 h post‐exercise	Blood sample
Kim et al.	5‐cm elastic cuffs inflated to an absolute measure of 200 mmHg	NA	1 min	1 min	All experiment days were separated by 4 days	All experiment days were separated by 4 days	Growth hormone, and cortisol	Initial post‐exercise	Blood sample
Kraemer et al.	11‐cm wide cuff was inflated to 20 mmHg below systolic blood pressure and for calf extension inflated to 40 mmHg greater than biceps curls occlusion pressure and in a continuous fashion	NA	1 min	1 min	Not reported	Not reported	Irisin	Initial post‐exercise	Blood sample
Larkin et al.	Kaatsu master mini, Soto sports plaza, Tokyo cuff inflated to an absolute measure of 220 mmHg	NA	1 min	1 min	Minimum 3 weeks separating the two test days	Minimum 3 weeks separating the two test days	Vascular endothelial growth factor, endothelial nitric oxide synthase, inducible nitric oxide synthase, and neuronal nitric oxide synthase	4‐ and 24‐hours post‐exercise	Muscle and blood sample
Laurentino et al. A	17.5 cm wide nylon cuff with an 80% AOP (average AOP 94.80 ± 10.30 mmHg) in a continuous fashion	NA	1 min	1 min	Two training sessions pr. week for 8 weeks	Two training sessions pr. week for 8 weeks	Growth hormone, insulin‐like growth factor‐1, testosterone, and cortisol	15‐minutes post‐exercise	Blood sample
Laurentino et al. A	17.5‐cm wide nylon cuff with an 80% AOP (average AOP 94.80 ± 10.30) in a continuous fashion	NA	1 minute	90 seconds	Two training sessions pr. week for 8 weeks	Two training sessions pr. week for 8 weeks	Growth hormone, insulin‐like growth factor‐1, testosterone, and cortisol	15‐minutes post‐exercise	Blood sample
Lima et al.	6.5‐cm cuff was inflated to 100% AOP (average AOP 232 ± 8 mmHg) in a continuous fashion	Na	Not reported	Not reported	3 training sessions pr week for 8 weeks	3 training sessions pr week for 8 weeks	Reduced glutathione, protein carbonyls	Initial post‐exercise	Blood sample
Madarame et al.	4‐cm elastic bands inflated to an absolute pressure of 200 mmHg in a continuous fashion	NA	30 s	30 s	NA	NA	Growth hormone, testosterone, and noradrenaline	Initial, 15‐ and 30‐minutes post‐exercise	Blood sample
Manini et al.	11‐cm wide blood pressure cuff were individualized to 1.5 times the brachial systolic blood pressure (cuff inflation range: 135 ‐ 186 mmHg) in a continuous fashion	NA	2 min	2 min	4 days separating each training sessions with an average of 13 days	4 days separating each training sessions with an average of 13 days	Growth hormone, and insulin‐like growth factor‐1	5‐, 15‐ and 35‐minutes post‐exercise	Blood sample
Neto et al. A	6‐cm wide pneumatic cuffs inflated to 1.3 times greater than individual systolic blood pressure (mean systolic blood pressure: 123.83 ± 9.7) in a continuous fashion	NA	30 s	2 min	Trial days were separated by between 72 and 96 h	Trial days were separated by between 72 and 96 h	Creatine phosphokinase, and protein carbonyl	Initial, 24‐ and 48 h post‐exercise	Blood sample
Neto et al. B	6‐cm wide pneumatic cuffs inflated to 1.3 times greater than individual systolic blood pressure (mean systolic blood pressure: 123.83 ± 9.7) in a intermittent fashion	NA	30 s	2 min	Trial days were separated by between 72 and 96 h	Trial days were separated by between 72 and 96 h	Creatine phosphokinase, and protein carbonyl	Initial, 24‐ and 48 h post‐exercise	Blood sample
Ozaki et al.	3‐cm wide elastic cuff inflated to an absolute pressure of 160 mmHg in a continuous fashion	NA	30 s	2–3 min	3 training sessions pr week for 6 weeks	3 training sessions pr week for 6 weeks	Endothelial nitric oxide synthase, and noradrenaline	Initial and 30 min post‐exercise	Blood sample
Ramis et al.	16‐cm wide cuff were inflated to 20 mmHg below systolic blood pressure and for knee extension cuffs were inflated to 40 mmHg above the applied pressure for elbow flexion	NA	2 min	2 min	NA	NA	Neuronal nitric oxide synthase, and inducible nitric oxide synthase	Initial post‐exercise	Blood sample
Reeves et al.	A custom designed narrow cuff was inflated to 20 mmHg below acute systolic pressure during biceps curls (mean arm occlusion time: 341 ± 4.5 seconds) and during calf extension the cuff was inflated to 40 mmHg above the arm occlusive pressure (mean leg occlusion time: 387 ± 13.1 seconds) in a continuous fashion. Occlusion pressure not reported	NA	1 min	1 min	Not reported	Not reported	Growth hormone, testosterone, and cortisol	Initial and 15 minutes post‐exercise	Blood sample
Sharifi et al. A	Not reported but they used an absolute pressure of 110 mmHg for the arms and 180 mmHg for the legs in a continuous fashion	NA	45 s	1 min	NA	NA	Growth hormone, testosterone, and vascular endothelial growth factor	Initial post‐exercise	Blood sample
Sharifi et al. B	Not reported but they used an absolute pressure of 110 mmHg for the arms and 180 mmHg for the legs in a continuous fashion	NA	45 s	1 min	NA	NA	Growth hormone, testosterone, and vascular endothelial growth factor	Initial post‐exercise	Blood sample
Takano et al.	3.3‐cm wide cuff inflated to 1.3 times higher than systolic blood pressure (Range: 160–180 mmHg) in a continuous fashion	NA	20 s	20 s	Trial days were separated by 2‐4 weeks	Trial days were separated by 2–4 weeks	Noradrenaline, growth hormone, insulin‐like growth factor‐1, vascular endothelial growth factor, ghrelin	Initial, 10, and 30‐min post‐exercise	Blood sample
Takarada et al.	9‐cm wide cuff inflated to a mean pressure of 218 ± 34.4 mmHg in a continuous fashion. Method not reported	NA	1 min	1 min	2 times pr week for 8 weeks	2 times pr week for 8 weeks	Growth hormone	15 minutes post‐exercise	Blood sample
Takarada et al.	3.3‐cm wide cuff inflated to a mean pressure 214 ± 18.9 mmHg) in a continuous fashion. Method not reported	NA	30 s	30 s	Trial days were separated by 7 days	Trial days were separated by 7 days	Growth hormone, noradrenaline, interleukin‐6, and creatine phosphokinase	Initial, 15‐ and 45‐minutes post‐exercise	Blood sample
Vilaça‐Alves	10‐cm and a 6‐cm wide cuff were attached to the legs and arm, respectively. 120% SBPr was used for the half‐squat and 100 SBPr was used for beanch press (SBPr 121.40 ± 4.55). The cuff was applied in an intermittent fashion	NA	30 s	90 s	Trial days were separated by 72 h	Trial days were separated by 72 h	Growth hormone, total testosterone, and cortisol	Initial and 15 min post‐exercise	Blood sample
Yinghao et al.	12‐cm wide pneumatic cuff inflated to 70% of AOP with a mean 70% AOP of: 137.8 ± 9.2.	NA	1 min	1 min	Trial days were separated by 72 h	Trial days were separated by 72 h	Growth hormone, insulin‐like growth factor‐1, Testosterone	Initial, 15‐ and 30‐min post‐exercise	Blood sample
Zhao et al.	Cuff was inflated to 130% of systolic blood pressure (mean systolic blood pressure: 114.86 ± 5.37). Not reported if it was applied in a continuous or intermittent fashion	NA	2 min	2 min	8‐week training program 5 days a week	8‐week training program 5 days a week	Vascular endothelial growth factor, and interleukin‐6	Initial post‐exercise	Blood sample

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Note: Table of training data presented in mean and standard deviation.

Abbreviations: AOP, arterial occlusion pressure; FFRE, heavy‐load and low‐load free flow resistance exercise; LL‐BFFRE, low‐load blood flow restricted exercise; NA, not applicable; Rest, inter‐set rest.

3.3. Risk of bias and quality of reporting assessment

All studies were assessed for risk of bias using ROB2 ⁶⁶ , ⁶⁷ and ROBINS‐I. Of the 20 studies assessed by ROB2, 10 studies received “Some concern” in overall bias, while 10 studies scored “High risk of bias.” For the 9 studies assessed by ROBINS‐I, 6 studies scored “Moderate risk of bias” with 3 studies receiving a “Serious risk of bias.” Tables are presented in Supplementary Data—Risk of bias assessment. TESTEX was used to assess study quality and study reporting for training intervention studies. ⁶⁴ Study quality scored an average of 2.71/5, with an average score of 4.89/10 for study reporting. The overall average TESTEX score was 7.60/15 (Table 4).

TABLE 4.

Assessment of study quality and reporting.

		Study quality						Study reporting
Study	Year	Eligibility criteria specified	Randomization specified	Allocation concealment	Groups similar at baseline	Blinding of assessor	Sum	Outcome assessed in 85% of participants	Intention‐to‐treat analysis	Between‐group statistical comparison reported	Point measures and measures of variability for all reported outcome	Activity monitoring in control groups	Relative exercise intensity remained constant	Exercise volume and energy expenditure	Sum	Total
Bemben et al.	2022	1	0	0	0	0	1	1	1	2	1	0	1	0	6	7
Boeneo et al.	2018	0	0	1	1	0	2	0	0	2	0	0	1	1	4	6
Burgera et al.	2018	1	0	1	1	0	3	2	0	2	1	0	1	1	7	10
Centner et al.	2018	1	0	0	1	0	2	2	0	2	1	0	1	0	6	8
Drummond et al.	2008	1	0	1	1	0	3	1	0	2	0	0	1	0	4	7
Ellefsen et al.	2015	0	0	1	1	1	3	1	0	2	0	1	1	1	6	9
Ferguson et al.	2018	0	0	0	1	0	1	0	0	2	0	0	1	1	4	5
Fujita et al.	2007	0	0	1	1	0	2	0	0	2	0	1	1	1	5	7
Garten et al.	2015	1	0	0	1	0	2	0	0	2	0	0	1	1	4	6
Goldfarb et al.	2008	1	0	0	1	0	2	2	0	2	0	0	1	0	5	7
Hughes et al	2020	0	1	1	1	0	3	3	1	2	1	1	1	1	10	13
Kim et al.	2014	1	0	1	1	0	3	0	0	2	1	1	1	1	6	9
Kraemer et al.	2005	1	0	0	1	0	2	2	0	1	0	0	1	0	4	6
Larkin et al.	2012	1	0	1	1	0	3	2	0	2	1	1	1	1	8	11
Laurentino et al.	2022	1	0	0	1	0	2	1	0	2	0	0	1	0	4	6
Lima et al.	2021	1	0	1	1	0	3	2	1	2	1	1	1	1	9	12
Madarame et al.	2008	0	0	1	1	0	2	0	0	2	0	0	0	1	3	5
Manini et al.	2012	1	0	1	1	0	3	0	0	2	0	0	1	1	4	7
Neto et al.	2018	1	0	1	1	0	3	0	0	2	0	0	1	1	4	7
Ozaki et al.	2013	1	0	1	1	1	4	0	0	2	1	1	0	1	5	9
Ramis et al.	2020	1	0	1	1	1	4	2	0	2	1	0	0	1	6	10
Reeves et al.	2006	1	0	0	1	0	2	2	0	1	0	0	1	1	5	7
Shariffi et al.	2020	1	0	1	1	0	3	0	0	2	1	0	0	1	4	7
Takano et al.	2005	1	0	0	1	0	2	0	0	2	1	0	1	0	4	6
Takarada et al.	2004	0	0	0	1	0	1	1	0	0	0	0	1	0	2	3
Takarada et al.	2000	0	0	0	1	0	1	1	0	0	0	0	0	0	1	2
Vilaça‐Alves	2023	1	0	0	1	0	2	1	0	2	1	0	1	1	6	8
Yinghao et al.	2021	1	1	0	1	1	4	2	1	2	0	0	1	0	6	10
Zhao et al.	2020	1	1	1	1	0	4	0	0	2	1	0	1	0	5	8

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Note: Table reporting the study quality and study reporting using the tool for assessment of study quality and reporting in exercise (TESTEX) assessment tool for training intervention studies. The score ranges from 0 to 15, where 15 represents the best score.

3.4. Synthesis of meta‐analysis data

A total of six different hormones along with two immune system and two oxidative stress markers were examined in the present meta‐analysis. Overall heterogeneity was generally high, and only two factors (creatine phosphokinase at the initial post‐exercise phase and testosterone at the late phase) scored low heterogeneity with an I ² of 0% and 4%, respectively, whereas two analyses had moderate‐to‐substantial heterogeneity scores (I ² = 52%–56%). All other analyses demonstrated substantial‐to‐considerable heterogeneity scores (I ² = 67%–94%).

3.5. Hormonal responses to LL‐BFRRE

Thirteen studies investigated the acute GH response at either one or all timepoints at the initial (n = 11), intermediate (n = 9), and late (n = 7) post‐exercise phase following acute bouts of LL‐BFRRE compared to FFRE. ³⁵ , ⁴³ , ⁴⁴ , ⁴⁵ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ There was no difference in GH plasma production in the initial post‐exercise phase (SMD = 0.64 [95% CI ‐0.23, 1.51]), whereas significant differences were observed in the intermediate (SMD = 2.04 [95% CI 0.87, 3.22]) and late (SMD = 2.64 [95% CI 1.13, 4.16]) time intervals post‐exercise. Subgroup analysis demonstrated a borderline significant increase in GH plasma production at the initial phase (SMD = 1.69 [95% CI ‐0.03, 3.42]), whereas significant increases were observed at intermediate (SMD = 3.39 [95% CI 1.54, 5.24]) and late (SMD = 3.55 [95% CI 1.59, 5.52]) post‐exercise phases for LL‐BFRRE compared to LL‐FFRE. In contrast, no difference in plasma GH content was demonstrated at any timepoint when comparing LL‐BFRRE to HL‐FFRE. Meta‐analysis for initial, intermediate, and late responses of GH are presented in Figure 2. Subgroup analysis for study design was performed where only randomized controlled and crossover trials were included in the analysis (excluding non‐randomized trials). Four studies were excluded ⁴³ , ⁴⁴ , ⁶⁹ , ⁷⁷ with no overall effect on the results when only including randomized trials (see Supplementary Data—Forest plots subgroup analysis).

Forest plot for growth hormone production initial (<10 min), intermediate (10–20 min), and late (>30 min) phase post‐exercise. Data are based on mean change score (pre‐ and post‐exercise) and standard deviation for the change scores. The meta‐analysis is based on a random‐effects model and data are presented using standardized mean difference, SMD. A subgroup analysis was performed on load intensity with the total combined effect presented with the lowest rhombi. Parentheses, 95% confidence interval. FFRE, free flow resistance exercise; HL‐FFRE, heavy‐load free flow resistance exercise; LL‐BFRRE, low‐load blood flow restriction resistance exercise; LL‐FFRE, low‐load free flow resistance exercise.

Nine studies measured acute testosterone responses following LL‐BFRRE compared to FFRE in the initial (n = 7), intermediate (n = 6), and late (n = 4) post‐exercise time intervals. ³⁵ , ⁴⁴ , ⁴⁵ , ⁴⁶ , ⁷⁰ , ⁷¹ , ⁷⁴ , ⁷⁶ , ⁷⁸ No differences in testosterone plasma levels were observed in the initial (SMD = 0.35 [95% CI −0.34, 1.05]) and intermediate (SMD = 0.55 [95% CI −0.26, 1.36]) post‐exercise phase when comparing LL‐BFRRE to overall FFRE. Subgroup analysis on load intensity did not demonstrate any difference at the initial and intermediate post‐exercise time intervals between LL‐BFRRE and LL‐FFRE or HL‐FFRE, respectively. However, a significant increase in testosterone plasma levels was observed at the late (SMD = 0.60 [95% CI 0.09, 1.10]) post‐exercise phase for LL‐BFRRE compared to LL‐FFRE. Initial, intermediate, and late responses of testosterone are compared between exercise protocols in Figure 3. Subgroup analysis on study design (randomized controlled/crossover trials vs. non‐randomized trials) resulted in one study being excluded. ⁴⁴ This did not affect the overall results at any timepoint (see Supplementary Data—Forest plots subgroup analysis).

Forest plot for testosterone production initial (<10 min), intermediate (10–20 min), and late (>30 min) phase post‐exercise. Data are based on mean change score (pre‐ and post‐exercise) and standard deviation for the change scores. The meta‐analysis is based on a random‐effects model and data are presented using standardized mean difference, SMD. A subgroup analysis was performed on load intensity with the total combined effect presented with the lowest rhombi. Parentheses, 95% confidence interval. FFRE, free flow resistance exercise; HL‐FFRE, heavy‐load free flow resistance exercise; LL‐BFRRE, low‐load blood flow restriction resistance exercise; LL‐FFRE, low‐load free flow resistance exercise.

A total of seven studies compared the initial (n = 6), intermediate (n = 4), and late (n = 1) responses in post‐exercise plasma cortisol levels between LL‐BFRRE and overall FFRE. ³⁵ , ⁴⁴ , ⁴⁶ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ Production in cortisol plasma levels did not differ between LL‐BFRRE and FFRE at the initial (SMD = 0.65 [95% CI −0.00, 1.31]) and intermediate (SMD = 0.60 [95% CI −0.47, 1.68]) post‐exercise phases. Pertaining to the single study at the late post‐exercise timepoints, an increase in plasma cortisol levels was detected for LL‐BFRRE compared to LL‐FFRE. ³⁵ No differences in cortisol plasma levels were demonstrated at the initial and intermediate post‐exercise phases when comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE, respectively. Initial and intermediate responses of cortisol compared across exercise protocols are presented in Supplementary Data—Forest plots. Subgroup analysis on study design (randomized controlled/crossover trials vs. non‐randomized trials) excluded one study, ⁴⁴ but did not change the overall results (see Supplementary Data—Forest plots subgroup analysis).

A total of seven studies evaluated acute IGF‐1 secretion at initial (n = 6), intermediate (n = 3), and late (n = 3) timepoints post‐exercise. ³⁵ , ⁴⁵ , ⁴⁶ , ⁷⁰ , ⁷⁵ , ⁷⁷ , ⁷⁹ There was no significant difference in IGF‐1 plasma levels at the initial (SMD = 0.61 [95% CI −0.43, 1.65]) and intermediate (SMD = 0.34 [95% CI −0.41, 1.09]) post‐exercise phases when comparing LL‐BFRRE to overall FFRE. When performing subgroup analysis based on loading intensities, there was a borderline significant increase in IGF‐1 plasma levels at the initial (SMD = 1.14 [95% CI −0.15, 2.42]) and intermediate (SMD = 0.88 [95% CI −0.14, 1.91]) post‐exercise timepoints in LL‐BFRRE compared to LL‐FFRE. However, when comparing LL‐BFRRE to HL‐FFRE at the intermediate timepoint, a single study reported increased IGF‐1 plasma levels for the HL‐FFRE compared to the LL‐BFRRE. ⁷⁰ Otherwise, no differences in IGF‐1 plasma levels were detected at any other timepoints when comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE. In addition, a single study that was not included in the meta‐analysis evaluated IGF‐1 on muscle mRNA expression comparing LL‐BFRRE versus HL‐FFRE at 3 h post‐exercise and found no difference between the two exercise protocols. ⁷⁹ Meta‐analyses for initial, intermediate, and late responses of IGF‐1 are presented in Supplementary Data—Forest plots. Subgroup analysis on study design (randomized controlled trials vs. non‐randomized trials) excluded one study ⁷⁷ and did not demonstrate any changes in these results (see Supplementary Data—Forest plots subgroup analysis).

Vascular endothelial growth factor (VEGF) was examined in four studies at initial (n = 3), intermediate (n = 1), and late (n = 2) post‐exercise phase. ⁵⁰ , ⁷⁶ , ⁷⁷ , ⁸⁰ In the initial post‐exercise phase, VEGF production increased to a similar extent with LL‐BFRRE and overall FFRE (SMD = 1.54 [95% CI −0.47, 3.55]). In addition, a single study evaluated VEGF production and found an increase in VEGF plasma levels in favor of LL‐BFRRE compared to LL‐FFRE in the intermediate time intervals. ⁷⁷ Two studies examined the late post‐exercise effects, with one study observing increased VEGF plasma levels in favor of LL‐BFRRE compared to LL‐FFRE 30 min post‐exercise, ⁷⁷ and the other study reporting larger acute gains in muscle biopsy VEGF mRNA expression with LL‐BFRRE compared to LL‐FFRE at 4 and 24 h post‐exercise. ⁵⁰ Subgroup analysis was only performed for the initial post‐exercise phase. VEGF plasma levels were not elevated with LL‐BFRRE compared to LL‐FFRE (SMD = 2.76 [95% CI −1.11, 6.64]) nor between LL‐BFRRE and HL‐FFRE (SMD = 0.32 [95% CI −0.54, 1.19]). The meta‐analysis for these initial VEGF responses is presented in Supplementary Data—Forest plots. Subgroup analysis on study design (randomized controlled/crossover trials vs. non‐randomized trials) did not change the result of the meta‐analysis when excluding one non‐randomized study ⁷⁷ at the initial post‐exercise phase (see Supplementary Data—Forest plots subgroup analysis).

Noradrenalin was assessed in four studies during the initial (n = 4), intermediate (n = 3), or late (n = 4) post‐exercise time intervals. ⁴³ , ⁵¹ , ⁷⁴ , ⁷⁷ Comparing LL‐BFRRE to overall FFRE, there was no significant difference during the initial (SMD = 2.06 [95% CI −0.12, 4.24]) and late (SMD = 0.01 [95% CI −0.85, 0.86]) post‐exercise time intervals. A single study investigated LL‐BFRRE compared to HL‐FFRE in the initial and late post‐exercise time intervals and found no significant difference between groups. ⁵¹ Noradrenaline plasma levels increased in the initial post‐exercise phase in favor of LL‐BFRRE when compared to LL‐FFRE (SMD = 2.89 [95% CI 1.13, 4.65]) with no differences observed in the intermediate and late post‐exercise phases. The meta‐analysis for the initial, intermediate, and late responses of noradrenaline is presented in Figure 4. Subgroup analysis for study design (randomized controlled/crossover trials vs. non‐randomized trials) excluded two non‐randomized trials, ⁴³ , ⁷⁷ and did not impact the results at the initial (SMD = 0.58 [95% CI −1.95, 3.12]) and late (SMD = 0.20 [95% CI −1.45, 1.85]) post‐exercise phases (see Supplementary Data—Forest plots subgroup analysis). However, only one study remained for the intermediate post‐exercise phase, subgroup analysis which demonstrated a significant increase in plasma levels of noradrenalin for LL‐BFRRE. ⁷⁴

Forest plot for noradrenaline production initial (<10 min), intermediate (10–20 min), and late (>30 min) phase post‐exercise. Data are based on mean change score (pre‐ and post‐exercise) and standard deviation for the change scores. The meta‐analysis is based on a random‐effects model and data are presented using standardized mean difference, SMD. A subgroup analysis was performed on load intensity with the total combined effect presented with the lowest rhombi. Parentheses, 95% confidence interval. FFRE, free flow resistance exercise; HL‐FFRE, heavy‐load free flow resistance exercise; LL‐BFRRE, low‐load blood flow restriction resistance exercise; LL‐FFRE, low‐load free flow resistance exercise.

3.5.1. Ghrelin, sex hormone binding globulin, androstenedione, β‐endorphine, and irisin

A single study compared the responses of ghrelin between LL‐BFRRE and LL‐FFRE in the initial, intermediate, and late post‐exercise phases. ⁷⁷ There was no effect of time and no difference between the two training modalities as ghrelin could not be detected in the LL‐FFRE group. In a single study, plasma sex hormone binding globulin (SHBG) and androstenedione were measured in the initial and late post‐exercise time intervals, where each leg were randomized to either LL‐BFRRE or HL‐FFRE. No differences were observed between the two training protocols for either SHBG or androstenedione. ⁷²

A single study explored the acute response of β‐endorphine and compared LL‐BFRRE (40% AOP) and LL‐BFRRE (80% AOP) to LL‐FFRE and HL‐FFRE in the initial and late (24 h) post‐exercise time intervals. ⁴⁹ Acute increases in β‐endorphine plasma levels were observed for LL‐BFRRE (40% AOP) and LL‐BFRRE (80% AOP) compared to LL‐FFRE and HL‐FFRE, whereas no differences were observed at the late time interval between any groups. In a single study, irisin was observed in the initial and intermediate post‐exercise time intervals following LL‐BFRRE and HL‐FFRE. ⁸¹ A significant increase in favor of LL‐BFRRE compared to HL‐FFRE was observed in the intermediate post‐exercise time interval, whereas no significant difference could be observed in the initial post‐exercise phase. ⁸¹

3.6. Immune system responses to LL‐BFRRE

IL‐6 was evaluated by three studies with a focus on initial (n = 3), intermediate (n = 1), and late post‐exercise effects (n = 1). ⁴³ , ⁴⁷ , ⁸⁰ Subgroup analysis of IL‐6 showed no significant difference between LL‐BFRRE and LL‐FFRE (SMD = 1.79 [95% CI −0.58, 4.17]) in the initial post‐exercise phase. A single study evaluated the effect of LL‐BFRRE compared to HL‐FFRE but was unable to detect any measurable levels of IL‐6 post‐exercise. ⁴⁷ Furthermore, a single study examined intermediate and late IL‐6 responses and found no significant difference between the two exercise protocols at the intermediate timepoint, whereas elevated IL‐6 responses were observed in the late post‐exercise phase (30‐minutes post‐exercise) in favor of LL‐BFRRE compared to LL‐FFRE. ⁴³ Meta‐analysis for initial responses of IL‐6 is presented in Supplementary Data—Forest plots. Subgroup analysis on study design (randomized controlled/crossover trials vs. non‐randomized trials) excluded one non‐randomized trial, ⁴³ leaving only a single study reporting increased IL‐6 plasma levels in the initial post‐exercise phase ⁸⁰ (see Supplementary Data—Forest plots subgroup analysis).

IL‐15 plasma concentrations were evaluated in a single study ⁴⁷ during the initial and late (1 and 24 h) post‐exercise phases comparing LL‐BFRRE to LL‐FFRE, and HL‐FFRE. No acute elevations in IL‐15 were observed at any timepoints or between any training protocols. ⁴⁷

Creatine phosphokinase (CK) was investigated in two studies, ⁴³ , ⁴⁸ reporting no differences in CK between LL‐BFRRE and overall FFRE in the initial (SMD = −0.03 [95% CI −0.57, 0.52]) and late (SMD = −1.32 [95% CI −2.72, 0.09]) post‐exercise time intervals. However, an elevated CK response was observed for HL‐FFRE compared to LL‐BFRRE in the late post‐exercise phase (SMD = −2.03 [95% CI −2.83, 1.24]). One study investigated CK at intermediate post‐exercise time points with no difference between LL‐BFRRE and LL‐FFRE. ⁴³ Meta‐analysis for initial and late responses of CK is presented in Supplementary Data—Forest plots. Subgroup analysis performed on study design (randomized controlled/crossover trials vs. non‐randomized trials) excluded one study ⁴³ and did not change the results (see Supplementary Data—Forest plots subgroup analysis).

3.6.1. 2‐Arachidonoylglycerol, decorin, superoxide dismutase, and catalase

2‐Arachidonoylglucerol (2‐AG) was evaluated in a single study comparing LL‐BFRRE (40% AOP) and LL‐BFRRE (80% AOP) to LL‐FFRE and HL‐FFRE in the initial and later (24 h) post‐exercise time intervals. ⁴⁹ No between‐group differences in 2‐AG plasma levels were noted in the initial and late post‐exercise time intervals although HL‐FFRE was found to be significantly reduced compared to pre‐exercise levels. ⁴⁹

Decorin was assessed in a single study comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE in the acute and late (1 and 24 h) post‐exercise time intervals. ⁴⁷ No significant between‐group difference was found but there was a significant increase in the initial post‐exercise phase compared to pre‐exercise for all groups.

Superoxide dismutase (SOD) and catalase were investigated in a single study comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE in the initial post‐exercise phase. ⁸² Initial post‐exercise responses for SOD were reduced for LL‐BFRRE but not LL‐FFRE compared to HL‐FFRE. ⁸²

For catalase, plasma levels were greater with LL‐FFRE compared to LL‐BFRRE and HL‐FFRE. There was a significant reduction from pre‐ to post‐exercise following LL‐FFRE with no changes observed following acute LL‐BFRRE and HL‐FFRE. ⁸²

3.7. Oxidative stress responses to LL‐BFRRE

NO was investigated in two studies in the initial (n = 2) and late (n = 1) post‐exercise phases. ⁵¹ , ⁸² No differences were observed when comparing LL‐BFRRE to overall FFRE (SMD = −0.44 [95% CI −0.34, 1.22]). Subgroup analysis demonstrated no differences when comparing LL‐BFRRE to LL‐FFRE (SMD = 0.25 [95% CI −0.59, 1.09]) nor when comparing LL‐BFRRE to HL‐FFRE (SMD = −0.53 [95% CI −0.83, 1.89]). A single study investigated the acute NO response in the late post‐exercise time interval (30‐minute post‐exercise) and found no significant difference between LL‐BFRRE and HL‐FFRE. ⁵¹ Meta‐analysis for initial response of NO is presented in Supplementary Data—Forest plots. No subgroup analysis for study design (randomized controlled/crossover trial vs. non‐randomized trials) was performed as only randomized studies were included in the analysis. In addition, a single study ⁸³ evaluated nitrate and nitrite oxide (products of NO) plasma concentrations between LL‐BFRRE and HL‐FFRE at the initial post‐exercise phase and observed a significant increase from pre‐exercise to post‐exercise but no significant differences were observed between groups.

Protein carbonyls (PC) was assessed by three studies in the meta‐analysis during the initial (n = 3), intermediate (n = 1), and late (n = 1) post‐exercise time intervals. ⁴⁸ , ⁵² , ⁸⁴ All studies compared LL‐BFRRE to HL‐FFRE, revealing borderline significant increased plasma levels of PC for HL‐FFRE compared to LL‐BFRRE in the initial post‐exercise time interval (SMD = −1.50 [95% CI −3.19, 0.20]). Furthermore, a study evaluated the effect of LL‐BFRRE compared to HL‐FFRE at the intermediate post‐exercise time intervals but found no difference between LL‐BFRRE and HL‐FFRE. ⁸⁴ Finally, a single study evaluated delta values in PC following LL‐BFRRE compared to LL‐FFRE and HL‐FFRE in the initial post‐exercise phase. ⁸⁵ Significant increased delta plasma level values were observed for both LL‐FFRE and HL‐FFRE compared to LL‐BFRRE. Meta‐analysis for initial responses of PC is presented in Figure 5. Subgroup analysis performed on study design (randomized controlled/crossover trials vs. non‐randomized trials) did not change the results as discarding one non‐randomized study ⁸⁴ similarly resulted in a non‐significant difference (SMD = −1.55 [95% CI ‐4.01, 0.91]) between LL‐BFRRE and HL‐FFRE (see Supplementary Data—Forest plots subgroup analysis).

Forest plot for protein carbonyls production initial (<10 min) post‐exercise. Data are based on mean change score (pre‐ and post‐exercise) and standard deviation for the change scores. The meta‐analysis is based on a random‐effects model and data are presented using standardized mean difference, SMD. A subgroup analysis was performed on load intensity with the total combined effect presented with the lowest rhombi. Parentheses, 95% confidence interval. FFRE, free flow resistance exercise; HL‐FFRE, heavy‐load free flow resistance exercise; LL‐BFRRE, low‐load blood flow restriction resistance exercise; LL‐FFRE, low‐load free flow resistance exercise.

3.7.1. Glutathione, endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase, systemic reactive oxygen species, and local reactive oxygen species

Two studies assessed the glutathione response in the initial post‐exercise phase ⁸⁴ , ⁸⁵ and one study at the intermediate phase. ⁸⁴ One study found no significant difference between LL‐BFRRE and LL‐FFRE in the initial post‐exercise phase, ⁸⁵ however, both studies found greater gains in plasma glutathione concentrations for HL‐FFRE when compared to LL‐BFRRE in the initial post‐exercise phase. ⁸⁴ , ⁸⁵ In the intermediate post‐exercise phase, no differences were noted in glutathione plasma levels between LL‐BFRRE and HL‐FFRE. ⁸⁴

Two studies investigated acute endothelial nitric oxide synthase (eNOS) responses in the late (2, 4, and 24 h) post‐exercise phase comparing LL‐BFRRE to LL‐FFRE. ⁵⁰ , ⁸⁶ One study reported no significant difference in muscle eNOS mRNA expression between LL‐BFRRE and LL‐FFRE at 2 h post‐exercise. ⁸⁶ At 4 h post‐exercise, one study reported an increased muscle eNOS mRNA expression for LL‐BFRRE compared to LL‐FFRE, ⁸⁶ whereas another study found no significant difference in muscle mRNA expression at the 4 h post‐exercise between LL‐BFRRE and LL‐FFRE. ⁵⁰ Furthermore, no between‐group differences were observed 24 h post‐exercise. ⁵⁰

One study evaluated late phase (4 and 24 h post‐exercise) mRNA expression in neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) following LL‐BFRRE compared to LL‐FFRE. ⁵⁰ Increases in nNOS but not iNOS were observed at 4 h post‐exercise, whereas both nNOS and iNOS were upregulated at 24 h post‐exercise, with all responses being more upregulated with LL‐BFRRE compared to LL‐FFRE. ⁵⁰

Systemic and local ROS were investigated in a single study comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE in the initial post‐exercise phase. ⁸⁷ For local ROS production (plasma), no significant between‐group differences was demonstrated. Likewise, no significant between‐group differences could be observed for systemic (plasma) ROS production although elevated plasma ROS levels were observed in LL‐BFRRE group in the initial post‐exercise phase compared to baseline. ⁸⁷

4. DISCUSSION

This systematic review and meta‐analysis is the first to investigate the magnitude and timing of hormonal, immune, and oxidative stress responses evoked by acute low‐load blood flow‐restricted resistance exercise (LL‐BFRRE) in healthy adults. The main finding was that acute GH, testosterone, and noradrenaline responses were enhanced with LL‐BFRRE compared to load‐matched free‐flow resistance exercise (LL‐FFRE), but in most cases of similar magnitude compared to conventional heavy‐load resistance exercise (HL‐FFRE). Furthermore, acute HL‐FFRE produced more elevated CK levels compared to LL‐BFRRE in the late post‐exercise phase. The present meta‐analysis also demonstrated that LL‐BFRRE and HL‐FFRE were equally effective in inducing a wide range of acute hormonal responses. Notably, GH (intermediate and late post‐exercise phases), testosterone (late), and noradrenaline (initial) were elevated with LL‐BFRRE compared to intensity‐ and volume‐matched FFRE. These novel synthesized data have important implications for (i) expanding our insight into the adaptive mechanisms of LL‐BFRRE, and (ii) optimizing the design of LL‐BFRRE protocols within the fields of sports conditioning and clinical rehabilitation of muscles and tendons. ²⁶ , ⁴³ , ⁸⁸

4.1. Hormonal responses

4.1.1. Growth hormone

GH has been thought to play an essential role in inducing muscle hypertrophy, ⁵³ , ⁸⁹ although there is increasing evidence that puts its role into question. ⁵⁵ , ⁵⁶ , ⁹⁰ , ⁹¹ Some evidence suggests that GH may increase serum IGF‐1 due to its conversion in the liver. In contrast, exogenous and gene transfer IGF‐1 has been shown to increase muscle fiber volume in mice. ⁹² , ⁹³ Despite the fact that GH does not seem to influence muscle hypertrophy and muscle strength in adult humans, the available evidence does suggest that GH can positively influence type I collagen synthesis. ⁵⁶ , ⁹⁴ Therefore, training regimes that increase the upregulation of exercise‐induced GH could be beneficial in the training and rehabilitation of tendon collagen tissue including exercise conditions in healthy athletes (increased tendon size and stiffer tendon tissue) ³⁰ , ⁹⁵ while also being of potential interest in tendon rupture and tendinopathy. ⁹⁶

In the present meta‐analysis, GH was found to be acutely upregulated at the intermediate and late post‐exercise timepoints for both LL‐BFRRE and HL‐FFRE, supported by moderate‐to‐large effect sizes. In addition, we found that load intensity overall had an effect. Furthermore, we found a significantly greater effect on GH in favor of LL‐BFRRE compared to LL‐FFRE but with no difference between LL‐BFRRE and HL‐FFRE. These findings suggest that LL‐BFRRE may yield greater acute effects on GH secretion than intensity‐ and volume‐matched FFRE. Moreover, LL‐BFRRE and HL‐FFRE appeared equally effective in inducing GH responses with acute exercise. These GH responses may have important implications when designing resistance training protocols that promote tendon adaptations in athletes and various rehabilitation settings (i.e., tendinopathy).

4.1.2. Testosterone

Testosterone is an androgenic anabolic hormone, which in high endogenous amounts may positively affect muscle hypertrophy, strength gains, stimulating nervous system function, and other hormonal mechanisms such as GH and IGF‐1 ⁹⁷ with resistance training, ²⁰ , ⁹⁸ albeit others have reported negligible correlations. ⁹¹ Several studies have demonstrated that exogenous testosterone administration leads to significant increases in muscle mass and strength in a dose‐dependent manner ⁹⁹ , ¹⁰⁰ although testosterone levels following injections by far exceed the upregulation in endogenous testosterone secretion with acute and chronic resistance exercise. In the present meta‐analysis, we found no significant difference in testosterone production between LL‐BFRRE and overall FFRE at the initial and intermediate post‐exercise time intervals, and no statistically significant differences were observed in the magnitude of different exercise protocols on plasma testosterone at any time interval. In contrast, there was a significant upregulation of plasma testosterone when comparing LL‐BFRRE to LL‐FFRE at the late post‐exercise phase. These findings suggest that LL‐BFRRE may yield greater effects on acute endogenous testosterone secretion compared to intensity‐ and volume‐matched FFRE. Furthermore, the present data support the notion that LL‐BFRRE and HL‐FFRE are equally effective in inducing endogenous testosterone responses with acute exercise.

4.1.3. Cortisol

Cortisol is a catabolic glucocorticoid hormone widely known as a stress hormone that is regulated by the hypothalamic–pituitary–adrenal axis, ¹⁰¹ and is upregulated post‐exercise. ¹⁰² , ¹⁰³ Cortisol is crucial in the regulation of energy homeostasis and metabolism in skeletal muscle cells. Cortisol increases the availability of metabolic substrates during exercise while also protecting against immune cell activity and preserving vascular integrity. ¹⁰¹ Following an acute bout of exercise, there is potentially an increased sensitivity to glucocorticoids, which in turn decreases muscle damage and inflammation response, increase cytokine synthesis while also increase recovery. ¹⁰⁴ We found no difference in the production of cortisol in the initial response between LL‐BFRRE and overall FFRE in the present meta‐analysis, which may be due to a small number of studies.

4.1.4. Insulin‐like growth factor‐1

Insulin‐like growth factor 1 (IGF‐1) is a small protein peptide secreted by various structures, such as the liver and skeletal muscle. ¹⁰⁵ IGF‐1 is thought to indirectly influence many effects associated with resistance exercise and muscle hypertrophy. ⁹⁷ IGF‐1 has been associated with an increase in muscle protein synthesis, utilization of free fatty acids, improvements in insulin sensitivity, and it may play an essential role in exercise‐induced muscle hypertrophy ¹⁰⁶ , ¹⁰⁷ , ¹⁰⁸ and thereby increase in muscle strength. IGF‐1 may also increase collagen synthesis, ¹⁰⁹ , ¹¹⁰ as well as play a part in cognitive function, ¹¹¹ potentially through cerebral effects on neurogenesis and angiogenesis. ¹¹² , ¹¹³ The potential mechanism for muscle hypertrophy and increased collagen synthesis could be that IGF‐1 may be a determinant for initiating anabolic and signaling pathways ¹⁰⁸ and the fusion of satellite cells. ¹¹⁴ The present meta‐analysis revealed no significant difference in IGF‐1 between LL‐BFRRE and overall FFRE at any timepoint post‐exercise or in subgroup analysis on load intensity. This could be due to the limited number of studies examined and a high degree of heterogeneity across these studies.

4.1.5. Vascular endothelial growth factor

Skeletal muscle cells produce and secrete VEGF, have VEGF receptors, and respond to VEGF stimulation. VEGF is essential for capillary maintenance, ¹¹⁵ endothelial cell and myofiber survival, ¹¹⁶ exercise‐induced angiogenesis, ¹¹⁷ , ¹¹⁸ and muscular endurance. ¹¹⁹ Because contractile activity increases muscle metabolism, angiogenesis could be considered a secondary consequence of the metabolic demands imposed by the increased muscle mass. ¹²⁰ Muscle fiber hypertrophy involves the accumulation of protein mass, and angiogenesis is necessary to deliver oxygen and nutrients to and remove metabolic waste from the muscle fibers. ¹²⁰ In this meta‐analysis, we found no significant upregulation in VEGF for LL‐BFRRE compared to overall FFRE at the initial post‐exercise phase. Only a few studies have investigated the acute effects of LL‐BFRRE compared to LL‐FFRE on VEGF synthesis at all post‐exercise timepoints or in subgroup analysis on load intensity. These findings could be due to the limited number of studies examined and the high degree of heterogeneity across these studies.

4.1.6. Noradrenaline

Noradrenaline is both a hormone and a neurotransmitter that transmits nerve signals to, for example, muscle cells as part of the sympathetic nervous system. ¹²¹ An elevation in noradrenaline outflow to the blood vessels of contracting and resting skeletal muscle may play a key role in blood pressure regulation while simultaneously being a marker for greater sympathetic nervous system activation. ¹²² Secondly, noradrenaline has been demonstrated to increase glycose production and uptake during moderate exercise, ¹²³ indicating that it plays an essential role in physical performance. This meta‐analysis found a significant amplified response in noradrenaline at the initial post‐exercise phase in favor of LL‐BFRRE compared to LL‐FFRE, whereas no significant increases were observed at any other timepoints or between exercise protocols. This could indicate that LL‐BFRRE induces higher activation of the sympathetic nervous system compared to LL‐FFRE, whereas similar responses were observed for HL‐FFRE.

4.1.7. Ghrelin, sex hormone binding globulin, androstenedione, β‐endorphine, and irisin

Ghrelin is a stomach‐derived hormone that stimulates the production of GH in combination with regulating various processes related to eating, body weight, and blood glycose regulation. ¹²⁴ Ghrelin is proposed to enhance exercise endurance by stimulating the sympathoadrenal system, increasing IGF‐1 levels, and/or increasing the availability of gluconeogenic substrates such as lactate to meet the energy demand of prolonged exercise. ¹²⁴ However, we only identified a single study investigating the acute ghrelin response following LL‐BFRRE compared to LL‐FFRE, with no significant difference between the two exercise modalities. ⁷⁷ This makes it difficult to conclude any effect on ghrelin production following LL‐BFRRE compared to conventional FFRE.

SHB‐globulin is a protein that releases testosterone into the circulation, while also being an important transport protein for testosterone and other steroids. SHBG also influences testosterone's binding capacity and bioavailability for diffusion across the cell membrane. ¹⁰¹ Androstenedione is a steroidal hormone produced in the female and male gonads and the adrenal glands. Androstenedione is a precursor hormone to testosterone and is thought to increase testosterone levels, thus contributing to the physiological and athletic advantages of testosterone. SHBG and androstenedione were evaluated by the same study with no significant difference in the production of SHB‐globulin and androstenedione between LL‐BFRRE and HL‐FFRE, ⁷² preventing any firm conclusions to be drawn. Similarly, the methodology in the study could explain the result as each leg was randomized to either LL‐BFRRE or HL‐FFRE, and exercises were performed on alternating days, which potentially could have influenced the results due to carryover effect.

β‐endorphin is a peptide that is primarily released from the anterior pituitary gland ¹²⁵ and is part of the endogenous opioid family. ¹²⁵ , ¹²⁶ Increased levels of β‐endorphin post‐exercise have an analgesic effect ¹²⁷ while also modulating (downregulating) the pain perception during exercise. ¹²⁶ Additionally, β‐endorphin has been shown to increase immune system function ¹²⁶ , ¹²⁸ and suppress pro‐inflammatory mediators. ¹²⁹ One study found a significant increase in β‐endorphin in favor of LL‐BFRRE compared to LL‐ and HL‐FFRE in the initial and at 24 h post‐exercise.49 It could be due to the metabolic stress and increased secretion of β‐endorphin that LL‐BFRRE induced a more pronounced analgesic effect compared to traditional LL‐FFRE and HL‐FFRE. Irisin is a peptide hormone that is acutely elevated following exercise. ¹³⁰ , ¹³¹

Irisin is composed of the cleaved product resulting from its precursor protein, FNDC5. The contraction of skeletal muscle during exercise can activate PGC‐1α to indirectly upregulate the expression of FNDC5, which correspondingly stimulates the generation and secretion of irisin. Irisin improves bone mass density, ¹³² glucose and lipid metabolism, mediates neuronal plasticity, potentially counteracting neurodegeneration, and it is important in maintaining cognitive function as well as ameliorates the effects of obesity‐driven inflammation, metabolic syndrome, and diabetes. ¹³³ A single study investigated the production of irisin following an acute bout of either LL‐BFRRE or HL‐FFRE, and found a significant increase in irisin at the intermediate post‐exercise phase. ⁸¹ Only a few studies have investigated the response of ghrelin, androstenedione, β‐endorphin, and irisin following acute LL‐BFRRE compared to FFRE; thus, furture studies are warranted.

4.2. Immune responses

4.2.1. Iinterleukin‐6

Iinterleukin‐6 (IL‐6) is a pleiotropic cytokine associated with the control and coordination of the immune system, and was recently also found to play a pivotal role in the regulation of visceral adipose tissue mass. ¹³⁴ Simultaneously, it is also believed that IL‐6 plays a critical role in the hypertrophy of muscle and connective tissue. IL‐6 has been detected locally at elevated concentrations in actively contracting muscle fibers, peritendinous tissue, and after increased workload, all of which are known to induce satellite cell activities and stimulate hypertrophy in muscle and connective tissue. ¹³⁵ , ¹³⁶ Tendon tissue is dominated by fibroblasts, which produce extracellular matrix components and release IL‐6. ¹³⁶ The final step in myokine‐IL‐6‐directed short‐term energy allocation is the augmentation of energy uptake in skeletal muscle cells and the suppression of energy uptake by other tissues. ¹³⁷ During and after exercise, muscular glucose uptake and insulin sensitivity are enhanced to meet the energetic demands of muscle contraction and muscle recovery and IL‐6 may potentially contribute to heightened insulin sensitivity after exercise. ¹³⁷ We found no significant upregulation of IL‐6 in LL‐BFRRE compared to LL‐FFRE. We only identified one study investigating IL‐6 between LL‐BFRRE and HL‐FFRE, but they were unable to detect IL‐6 at their post‐exercise measurement.

4.2.2. Interleukin‐15

Interleukin‐15 (IL‐15) is a helical protein that is expressed in different tissues, such as the liver, heart, and skeletal muscles, in particular skeletal muscle type II fibers. ¹³⁸ , ¹³⁹ Besides being important actor in the immune system, ¹⁴⁰ IL‐15 is also playing a vital role in skeletal muscle energy metabolism by increasing glycose uptake, ¹³⁹ body composition, ¹⁴¹ , ¹⁴² and potentially acting as an anabolic factor in skeletal muscle hypertrophy. ¹⁴³ , ¹⁴⁴ In the present literature analysis, we identified one study assessing IL‐15 plasma levels at the initial and late (1 h) post‐exercise phases. ⁴⁷ IL‐15 was acutely elevated to the same extent in LL‐BFRRE compared to LL‐FFRE and HL‐FFRE. Some studies have failed to detect any acute changes in IL‐15 following exercise ¹³⁸ , ¹⁴⁵ while others have reported IL‐15 to be elevated in the initial and late post‐exercise phases. ¹⁴⁶ , ¹⁴⁷ These differences in results could be due to methodological differences. Likewise, only one study compared the response of IL‐15 between LL‐BFRRE and FFRE. ⁴⁷ Thus, further studies are needed to understand the physiological responses of IL‐15 following acute bouts of LL‐BFRRE and FFRE.

4.2.3. Creatine phosphokinase

Creatine phosphokinase (CK) is an enzyme that catalyzes the reaction of creatine and adenosine triphosphate (ATP) into phosphocreatine and adenosine diphosphate in a reversible process that provides skeletal muscle and brain cells with considerable amounts of ATP, thereby making CK a central regulator of cellular energy homeostasis. During muscular injury, CK is leaked into the bloodstream and CK is consequently indicative of muscular damage, for example, following exercise. ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰ Individuals who regularly participate in exercise tend to have significantly elevated levels of CK compared to sedentary and moderately exercising individuals. ¹⁵¹ , ¹⁵² We found no significant difference in CK production when comparing LL‐BFRRE to overall FFRE at the initial and late post‐exercise phases. However, we found a single study that reported long‐lasting elevated levels of CK when comparing LL‐BFRRE and HL‐FFRE,48 indicating higher muscle damage performing HL‐FFRE. Participants performing LL‐BFRRE and HL‐FFRE also reported an increased rating of perceived exertion in the HL‐FFRE group, ¹⁵³ , ¹⁵⁴ , ¹⁵⁵ albeit others have found contradicting results. ¹⁵⁶ , ¹⁵⁷

4.2.4. 2‐Arachidonoylglycerol, decorin, superoxide dismutase, and catalase

2‐Arachidonoylglycerol is an endogenous cannabinoid that is upregulated during and after exercise. ¹⁵⁸ , ¹⁵⁹ 2‐AG is hypothesized to play an important role in homeostasis in thermoregulation, ¹⁶⁰ , ¹⁶¹ energy metabolism, ¹⁶² motor control, ¹⁶³ , ¹⁶⁴ learning and memory, ¹⁶³ , ¹⁶⁴ and in inflammation and immune response. ¹⁶⁵ 2‐AG is also known to induce a state of euphoria (runners high) due to its effect on the brain's reward system ¹⁶⁶ while also potentially increasing glucose and insulin sensitivity. ¹⁶⁷ 2‐AG was evaluated in a single study comparing LL‐BFRRE (40% AOP) and LL‐BFRRE (80% AOP) to LL‐FFRE and HL‐FFRE in the acute and late phases (24 h) post‐exercise with no between‐group differences, although a significant reduction compared to pre‐exercise levels was found for HL‐FFRE. ⁴⁹ This is in contrast to other studies that have found an increase in 2‐AG following aerobic exercise, ¹⁵⁸ , ¹⁶⁸ albeit other studies that did not report an increase following aerobic exercise. ¹⁶⁹ , ¹⁷⁰ These contrasting results may be due to methodological differences, such as exercise intensity. Likewise, it seems that LL‐BFRRE and LL‐FFRE and HL‐FFRE do not promote production of 2‐AG. However, only one study has investigated 2‐AG, and thus, no firm conclusions about the production of 2‐AG following LL‐BFRRE compared to LL‐FFRE or HL‐FFRE can be drawn.

Decorin is a small leucine‐rich proteoglycan that is primarily synthesized by fibroblasts, stressed vascular endothelial cells, and smooth muscle cells. ¹⁷¹ Decorin is coupled with collagen fibrils in all connective tissue and seems to increase tendon strength and modulus, ¹⁷² , ¹⁷³ , ¹⁷⁴ and skeletal muscle differentiation and regeneration. ¹⁷⁵ , ¹⁷⁶ , ¹⁷⁷ Decorin plays an important role in cell growth through modulation of growth factor activities. ¹⁷⁸ Strength training and anaerobic exercise upregulate decorin levels, ¹⁷⁹ which in turn regulate the expression of genes coding for muscle hypertrophy. ¹⁷⁸ Decorin was assessed in one study comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE in the initial and late phases (1 and 24 h) post‐exercise ⁴⁷ with no significant between‐group difference but a significant effect of time for all groups. Although based on a limited number of studies, the available data indicate that LL‐BFRRE induces similar acute decorin responses compared to LL‐FFRE and HL‐FFRE.

Superoxide dismutase (SOD) is an antioxidant enzyme that is positioned throughout human tissue, and embedded within different compartments of the cell. ¹⁸⁰ Endurance training and strength training increase SOD activity and mRNA expression for SOD isozymes in skeletal muscle. ¹⁸¹ , ¹⁸² Exercise dramatically increases oxygen consumption and causes oxidative stress, leading to an increased production of ROS such as superoxide anion (O₂ ^•–). ¹⁸³ SOD converts O₂ ^•– to hydrogen peroxide (H₂O₂), which is subsequently converted to water by catalase. ¹⁸⁴ It is hypothesized that SOD plays a significant role in the protection of cells against the damaging effects of superoxide radicals while being one of the most crucial enzymes in the antioxidant defense system. ¹⁸¹ , ¹⁸⁴ , ¹⁸⁵ SOD could partly reflect the dynamic balance between oxidation and anti‐oxidation in the body, and an abrupt change in SOD plasma levels might indicate an impaired balance between oxidation and anti‐oxidation in the body tissues. ¹⁸⁴ , ¹⁸⁵ SOD was investigated in a single study comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE in the initial post‐exercise phase. ⁸² Initial post‐exercise responses were reduced for LL‐BFRRE but not LL‐FFRE compared to HL‐FFRE.

Catalase is an antioxidant enzyme, similar to SOD, which is located in various types of human tissue and also exits in different compartments of the muscle cell. ¹⁸⁰ The primary function of catalase is to neutralize oxidants through the decomposition of free radicals into water and oxygen, thereby preventing the formation of H₂O_2. ¹⁸⁰ Exercise seems to increase the activity of catalase in skeletal muscles, ¹⁸² , ¹⁸⁶ , ¹⁸⁷ albeit some studies found a decrease or no change in catalase following exercise. ¹⁸⁸ , ¹⁸⁹ Catalase seems to act in synergy with glutathione peroxidase (GP). However, where GP is active during low levels of radicals, catalase seems only to be activated when higher concentrations of H₂O₂ are present in the cell. ¹⁸⁰ For catalase, post‐exercise increases were greater with LL‐FFRE compared to LL‐BFRRE and HL‐FFRE, and there was a significant reduction from pre‐ to post‐exercise following LL‐FFRE with no changes with LL‐BFRRE and HL‐FFRE. ⁸²

4.3. Oxidative stress responses

4.3.1. Nitric oxide

Nitric oxide (NO) is produced by the oxidation of one of the terminal guanidino nitrogen atoms of L‐arginine and through the nitrate‐nitrite‐nitric oxide pathway, ¹⁹⁰ and is catalyzed by NOS. ¹⁹¹ NO is a signaling gas molecule and is produced in various body parts, including skeletal muscle, after and during exercise. NO is an essential molecule for human metabolism as it plays an important role in several body functions. NO is known to control vasodilatation, ¹⁹² , ¹⁹³ blood rate, ¹⁹² , ¹⁹³ mitochondrial respiration, ¹⁹⁴ collagen synthesis, ¹⁹⁵ , ¹⁹⁶ , ¹⁹⁷ and muscle hypertrophy ¹⁹⁸ together with affecting glucose uptake ¹⁹² , ¹⁹⁹ in the skeletal muscles, thus enhancing sports performance and accelerating recovery. ¹⁹¹ NO was investigated in two studies,51, 82 and no significant difference was found between LL‐BFRRE and overall FFRE or HL‐FFRE. This could indicate that both training regimes (LL‐BFRRE vs. overall FFRE) induce similar NO responses. Albeit it seems that the metabolic stress of LL‐BFRRE increases the NO production, a study found a significant increase in NO production following HL‐FFRE compared to LL‐FFRE. ²⁰⁰

4.3.2. Protein carbonyls

Protein carbonyls (PC) is an indicator for ROS and are characterized as an irreversible post‐translational modification that produces a reactive carbonyl moiety in a protein, such as an aldehyde, ketone, or lactam. ²⁰¹ As cellular enzymes cannot repair carbonylated proteins, they tend to aggregate and, if not eliminated, result in cell death. ²⁰² Therefore, a fast clearance of carbonylated proteins is crucial for maintaining cell homeostasis. PC were assessed in three studies ⁴⁸ , ⁵² , ⁸⁴ and all studies compared LL‐BFRRE to HL‐FFRE. There was a borderline significant increase in PC in favor of HL‐FFRE at the initial phase (p = 0.08), however, no significant increase was observed at the intermediate post‐exercise phase. ⁸⁴ In support of the results from the meta‐analysis, another study also found an increase in delta % PC plasma level for HL‐FFRE at the initial phase compared to LL‐BFRRE. ⁸⁵ These results seem to suggest that HL‐FFRE induces increased oxidative stress markers at the initial phase compared to LL‐BFRRE. However, no significant increases were found in the meta‐analysis, possibly due to a limited number of studies and a high degree of heterogeneity.

4.3.3. Reactive oxygen species, neuronal nitric oxide synthase, inducible nitric oxide, endothelial nitric oxide synthase, and glutathione

Reactive oxygen species (ROS) represent a group of molecules that originate from molecular oxygen, and are formed by reduction oxidation reactions or electronic excitation. ²⁰³ A main hallmark of ROS formation is the production of superoxide (O₂ ⁻) and hydrogen peroxide (H₂O₂) in muscles during physical activity. ²⁰³ During rest, levels of ROS are generally considered to be low, with mitochondria thought to be the main origin of ROS generation in inactive muscles, ¹⁸⁰ , ²⁰⁴ however, ROS becomes elevated by muscular contraction by interaction with nicotinamide adenine dinucleotide oxidases. ⁵⁹ , ¹⁸⁰ ROS are regulators of muscle contractility and fatigue, and function as a second messenger for cell proliferation and differentiation while also playing a role in the homeostasis in skeletal muscle mass. ¹⁸⁰ , ²⁰⁴ , ²⁰⁵ As ROS is a free radical that can steal electrons from surrounding tissues and fluids, imbalances in ROS production can be troublesome for cells. It can lead to oxidative damage in macromolecules, such as DNA, proteins, and lipids. ²⁰⁶ Antioxidant enzymes, for example, SOD and catalase, play a key role in the protective mechanism. ²⁰⁶ Systemic and local ROS were investigated in a single study comparing LL‐BFRRE to LL‐FFRE and HL‐FFRE ⁸⁷ with no significant difference found between training modalities, although a significant increase from pre‐exercise to post‐exercise in systemic ROS was found for the LL‐BFRRE group. This could indicate that LL‐BFRRE induces higher metabolic demands and is a potential cause for hypertrophy associated with LL‐BFRRE, as ROS is a regulator for muscle cell signaling pathways. ¹⁸⁰ , ²⁰⁵

In mammals, three distinct isoforms exist: nNOS (type I), iNOS (type II), and eNOS (type III). nNOS is also an isoform of NOS located in skeletal muscles and nNOS is more predominant in fast‐twitch fibers than slow‐twitch fibers. ²⁰⁷ Signaling by nNOS is important for skeletal muscle homeostasis by regulating many important functions, such as muscle contraction and muscle metabolism. ²⁰⁷ , ²⁰⁸ In addition, nNOS also contributes to blood flow and oxygen delivery in synergy with eNOS, thus making the metabolic and blood supply demands of the contracting muscle more efficient, ²⁰⁹ making nNOS an essential regulator of skeletal muscle exercise performance, ²¹⁰ and nNOS may also play a regulatory role in tendon healing. ²¹¹ One study evaluated the initial and late (4 and 24 h post‐exercise) changes in nNOS following LL‐BFRRE compared to LL‐FFRE ⁵⁰ and found a significant increase in the late phase at both 4 and 24 h post‐exercise. As nNOS seems important for several physiological responses in muscle and tendon tissue, nNOS could be an essential factor for these adaptations in LL‐BFRRE.

iNOS is another isoform of NOS and is usually expressed at low levels in skeletal muscle tissue but can be increased by proinflammatory cytokines, for example, tumor necrosis factor‐alpha and interleukin 1‐beta. ²¹² iNOS pathways seem involved in sarcopenia and cathectic muscle loss, ²¹³ while also playing a part in muscle regeneration. ²¹⁴ iNOS has also demonstrated to enhance total collagen synthesis and accelerate tendon healing following injury. ¹⁹⁶ , ²¹⁵ , ²¹⁶ One study evaluated the initial and late (4 and 24 h post‐exercise) changes in iNOS following LL‐BFRRE compared to LL‐FFRE. ⁵⁰ iNOS did not increase at 4 h post‐exercise but was significantly increased 24 h post‐exercise in LL‐BFRRE compared to LL‐FFRE. This could indicate that LL‐BFRRE induces a significant upregulation of iNOS long term, and could potentially be a factor in muscle and tendon hypertrophy reported for LL‐BFRRE. However, only one study has investigated iNOS production following LL‐BFRRE compared to FFRE; thus, more studies are needed.

eNOS was initially thought to be located in endothelial cells only, however, it has subsequently been found to also be located in cardiomyocytes, adipocytes, and skeletal muscle fibers among other tissues. ²⁰⁷ Furthermore, the upregulation of eNOS might reduce the pressure of pulmonary blood vessels by shear‐induced endothelium‐dependent vasodilation. ²⁰⁹ Additionally, eNOS seems to have a regulatory role in tendon healing by boosting the blood flow to the granulation tissue as well as initiating angiogenesis at the injured site. ²¹⁵ Two studies comparing LL‐BFRRE to LL‐FFRE investigated eNOS in the late (2 and/or 4 h) post‐exercise phase. ⁵⁰ , ⁸⁶ A single study reported no significant difference between LL‐BFRRE and LL‐FFRE at 2 h post‐exercise. ⁸⁶ At 4 h post‐exercise, one study reported increased eNOS production with LL‐BFRRE compared to LL‐FFRE, ⁸⁶ whereas the other study found no significant differences between LL‐BFRRE and LL‐FFRE. ⁵⁰ Thus, results are contradicting, and it is difficult to draw any strict conclusion based on the available yet limited evidence.

Glutathione, a tripeptide consisting of γ‐L‐glutamyl‐L‐cysteinylglycine, is synthesized primarily in the hepatic cell. ²¹⁷ Exercise increases the depletion of glutathione by decreasing the reduced form and increasing the oxidized form of glutathione, which exacerbates oxidative stress. ²¹⁸ Glutathione is important in detoxification and is a determinant of redox signaling. Likewise, glutathione modulates cell proliferation, apoptosis, and immune function while also impacting fibrogenesis. ²¹⁷ In addition, evidence suggests that glutathione may be associated with aerobic energy metabolism ²¹⁹ , ²²⁰ and maintenance of muscle contraction. ²¹⁹ , ²²⁰ Two studies explored the response of glutathione in the initial post‐exercise phase, ⁸⁴ , ⁸⁵ while one of the studies also explored the response in the intermediate post‐exercise time interval. ⁸⁴ No significant difference was noted between LL‐BFRRE and LL‐FFRE in the initial time interval post‐exercise ⁸⁵ ; however, the study investigating LL‐BFRRE compared to HL‐FFRE found a significant increase in favor of HL‐FFRE at the initial and intermediate post‐exercise time intervals.

4.4. Subgroup analyses

Subgroup analyses were performed for load intensity (LL‐BFRRE vs. LL‐FFRE and HL‐FFRE) and study design (randomized controlled/crossover trials vs. non‐randomized trials). In the present analysis, load intensity seemed to influence some factors (GH, testosterone, noradrenaline, and CK) while other factors (cortisol, VEGF, IGF‐1, IL‐6, and PC) seemed to be unaffected. This could be due to different thresholds for exercise loads in the upregulation of certain physiological responses. Otherwise, the limited number of studies investigating hormone, immune, and oxidative stress responses could also be a factor, as subgroup analyses were difficult to perform and often produced large confidence intervals (95% CI), for example, for cortisol, VEGF, IL‐6, NO, and PC.

Subgroup analyses performed on study design (randomized controlled/crossover trial vs. non‐randomized trials) did not affect the overall results for most analyses, possibly due to the low number of non‐randomized studies included in the meta‐analysis.

4.5. Effects of BFR cuff pressure on acute hormonal, immune, and oxidative stress responses

A wide range of cuff pressures have been applied across BFRRE studies; thus, a clear consensus remains to be established, although individualized cuff pressures expressed as a fixed percentage of total arterial occlusion pressure (AOP) have been recommended. ²²¹ , ²²² In the present review, various cuff pressures were used, ranging from fixed absolute pressures (typically from 160 to 220 mmHg) or pressures 20% below or above systolic blood pressure, to individualized cuff pressures ranging from 40% to 150% AOP. Only a few studies have investigated the acute hormone, immune, and oxidative stress responses across different cuff pressures. ⁴⁵ , ⁴⁹ , ⁵² , ⁸⁰ Two studies found elevated hormone, immune, and oxidative stress responses in favor of high cuff pressures (70%–100% AOP) compared to lower cuff pressures (40%–50% AOP), ⁴⁵ , ⁵² whereas a single study did not find any differences between low (40% AOP) or high (80% AOP) cuff pressures. ⁴⁹ In contrast, elevated hormone and immune responses may occur with medium cuff pressures (65% AOP) compared to higher pressures (130% AOP). ⁸⁰ These results indicate that optimal cuff pressure ranges between 65% and 130% AOP, and pressures below and above this range may result in diminished hormone, immune, and oxidative stress responses with acute LL‐BFRRE.

4.6. Acute versus long‐term training‐induced hormonal, immune, and oxidative stress responses

Only a few studies have investigated how acute hormonal, immune, and oxidative stress responses transfer into long‐lasting responses after a continuous training regimen. ⁴⁶ , ⁵² , ⁷² , ⁸⁰ Two studies found increased acute hormone, immune, and oxidative stress responses at the end of an 8‐week training program. ⁵² , ⁸⁰ In contrast, two studies were unable to demonstrate differences in the hormone, immune, and oxidative stress responses, ⁴⁶ , ⁷² and one of the studies reported a reduced cortisol response after 6 weeks of LL‐BFRRE. ⁴⁶ Collectively, there is no clear pattern. Which warrants future studies that assess the effectiveness of longitudinal LL‐BFRRE on the acute hormone, immune, and oxidative stress responses over long‐lasting continuous training periods.

4.7. Timing of physiological responses in initial, intermediate, and late post‐exercise time intervals

Overall, there was an overall trend for greater hormone and immune responses in favor of LL‐BFRRE compared to overall FFRE in the initial (<10 min), intermediate (10–20 min), and late (≥30 min) post‐exercise phases. In contrast, oxidative stress responses demonstrated divergent results for LL‐BFRRE and overall FFRE.

For the initial response, LL‐BFRRE appeared to generally elicit amplified hormone and immune responses compared with LL‐FFRE, while being of similar magnitude compared with HL‐FFRE. Oxidative stress responses demonstrated no overall tendency, as the response differed vastly between markers; however, a borderline significant response (p = 0.08) was observed for elevated PC following acute HL‐FFRE. For the intermediate responses, enhanced hormone responses were generally observed in favor of LL‐BFRRE. No study investigated the acute training effect on various immune and oxidative stress markers in the intermediate post‐exercise phase. In the later post‐exercise time intervals, LL‐BFRRE appeared to generally elicit greater hormone responses compared with LL‐FFRE and of a similar magnitude compared with HL‐FFRE. In terms of acute immune and oxidative stress responses, LL‐BFRRE and LL‐FFRE generally induced similar responses, whereas HL‐FFRE was found to induce enhanced immune and oxidative stress responses during the late post‐exercise stage.

5. LIMITATIONS

There are inherent limitations to the present review as the studies included in this systematic review and meta‐analysis generally reflected a small sample size, which may have negatively affected the robustness of the statistical comparisons given that generally few studies were included in the different subanalyses performed. This underlines the need for further research into the physiological responses evoked by acute LL‐BFRRE to better understand the potential benefits and drawbacks of this training modality. We saw that there was generally high heterogeneity for the analyses (only three analyses scored low–to‐moderate heterogeneity) demonstrating a considerable variation between studies in terms of exercise protocols, cuff pressure, and training status of the participants, which impacts the present meta‐analysis data. Furthermore, all included studies scored some concerns to high risk of bias which may impact the confidence in the presented results. However, several studies scored relatively high on the TESTEX, which is designed to assess study quality, and study reporting for training studies as ROB2 and ROBINS‐1 may have some limitations in assessing the risk of bias in training studies. Notably, only studies on healthy individuals (mostly males) were included in the present systematic review and meta‐analysis; thus the hormone, immune, and oxidative stress response could be different in females and other different populations, for example, the elderly.

The present systematic review and meta‐analysis investigated the acute short‐term physiological responses evoked by LL‐BFRRE compared to FFRE. Therefore, no conclusions can be drawn about the progression or acclimatization of the physiological response nor the clinical effect of long‐term LL‐BFRRE training. Lastly, no published study was found to evaluate the effects of exercise bouts performed to failure when performing LL‐FFRE. Thus, it cannot be excluded that LL‐FFRE, if performed to failure, may lead to comparable physiological responses as observed for LL‐BFRRE.

6. CONCLUSION AND PERSPECTIVES

Acute low‐load blood flow‐restricted resistance exercise (LL‐BFRRE) produced increased endogenous production of growth hormone, testosterone, cortisol, insulin‐like growth factor‐1 (initial post‐exercise), vascular endothelial growth factor, noradrenaline, creatine phosphokinase (initial post‐exercise), and nitric oxide that is comparable to the responses evoked by conventional heavy‐load free‐flow resistance training (HL‐FFRE). In contrast, HL‐FFRE demonstrated increased levels of creatine phosphokinase (late post‐exercise phase) and borderline significant elevations in protein carbonyls (initial post‐exercise phase). Notably, LL‐BFRRE produced amplified acute responses in growth hormone (intermediate‐ and late‐phase post‐exercise), testosterone (late‐phase post‐exercise), and noradrenaline (initial post‐exercise) responses compared to intensity‐matched free‐flow resistance training (LL‐FFRE). The present hormone, immune, and oxidative stress responses were generally reported with a low level of evidence. To fully understand the potential acute physiological responses evoked by LL‐BFRRE, more high‐quality studies are needed.

In conclusion, the present systematic review and meta‐analysis demonstrate that LL‐BFR muscle exercise led to similar or enhanced acute changes in the endogenous production of a wide range of hormones, immune factors, and oxidative stress markers compared to conventional (i.e., free flow) muscle exercise involving heavy or low loading intensities. These observations support the emerging efficacy of LL‐BFRRE as an alternative or complementary training tool both in sports and clinical rehabilitation settings, especially for individuals unable to tolerate high levels of muscle–tendon–bone loading. Future studies should be conducted to investigate the impact of LL‐BFRRE more deeply on selected hormonal, immune, and oxidative stress responses, and explore the adaptive long‐term effects of these responses on muscle and connective tissue morphology and contractile function in both healthy and diseased populations.

AUTHOR CONTRIBUTIONS

M. H. Hjortshoej: Conceptualization; investigation; writing – original draft; writing – review and editing; methodology; formal analysis. Per Aagaard: Supervision; conceptualization; methodology; formal analysis; investigation; writing – review and editing. C. D. Storgaard: Conceptualization; methodology; investigation; writing – review and editing. H. Juneja: Conceptualization; methodology; formal analysis; supervision; writing – review and editing. J. Lundbye‐Jensen: Conceptualization; methodology; writing – review and editing. Peter S. Magnusson: Conceptualization; methodology; formal analysis; supervision; writing – review and editing; funding acquisition. Christian Couppé: Conceptualization; methodology; investigation; funding acquisition; writing – review and editing; formal analysis; supervision.

CONFLICT OF INTEREST STATEMENT

No financial or other conflict of interest is declared by any of the authors.

Supporting information

Appendix S1.

APHA-239-e14030-s002.zip^{(1.4MB, zip)}

Appendix S2.

APHA-239-e14030-s003.docx^{(699.4KB, docx)}

Appendix S3.

APHA-239-e14030-s001.docx^{(22.9KB, docx)}

Appendix S4.

APHA-239-e14030-s004.docx^{(23.4KB, docx)}

Appendix S5.

APHA-239-e14030-s005.pdf^{(1.2MB, pdf)}

ACKNOWLEDGMENTS

The present study was supported by RegionH, Bispebjerg Hospital, Center for Healthy Aging (Nordea Foundation), University of Copenhagen, The Association of Danish Physiotherapists, University College Absalon, and the Danish Medical Research Council.

Hjortshoej MH, Aagaard P., Storgaard CD, et al. Hormonal, immune, and oxidative stress responses to blood flow‐restricted exercise. Acta Physiol. 2023;239:e14030. doi: 10.1111/apha.14030

DATA AVAILABILITY STATEMENT

Data are available upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Appendix S1.

APHA-239-e14030-s002.zip^{(1.4MB, zip)}

Appendix S2.

APHA-239-e14030-s003.docx^{(699.4KB, docx)}

Appendix S3.

APHA-239-e14030-s001.docx^{(22.9KB, docx)}

Appendix S4.

APHA-239-e14030-s004.docx^{(23.4KB, docx)}

Appendix S5.

APHA-239-e14030-s005.pdf^{(1.2MB, pdf)}

Data Availability Statement

Data are available upon request.

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PERMALINK

Hormonal, immune, and oxidative stress responses to blood flow‐restricted exercise

M H Hjortshoej

P Aagaard

C D Storgaard

H Juneja

J Lundbye‐Jensen

S P Magnusson

C Couppé

Abstract

Introduction

Aim

Methods

Results

Conclusion

1. INTRODUCTION

2. MATERIALS AND METHODS

2.1. Study design and registration

2.2. Eligibility criteria

2.2.1. Population

2.2.2. Acute exercise protocols

2.2.3. Outcome variables

2.2.4. Study designs

TABLE 1.

2.3. Search methods and information sources

2.4. Study records

FIGURE 1.

2.5. Data extraction

2.6. Assessment of study quality and risk of bias

2.7. Data analysis

2.8. Subgroup analysis

3. RESULTS

3.1. Study selection

3.2. Included studies

TABLE 2.

TABLE 3.

3.3. Risk of bias and quality of reporting assessment

TABLE 4.

3.4. Synthesis of meta‐analysis data

3.5. Hormonal responses to LL‐BFRRE

FIGURE 2.

FIGURE 3.

FIGURE 4.

3.5.1. Ghrelin, sex hormone binding globulin, androstenedione, β‐endorphine, and irisin

3.6. Immune system responses to LL‐BFRRE

3.6.1. 2‐Arachidonoylglycerol, decorin, superoxide dismutase, and catalase

3.7. Oxidative stress responses to LL‐BFRRE

FIGURE 5.

3.7.1. Glutathione, endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase, systemic reactive oxygen species, and local reactive oxygen species

4. DISCUSSION

4.1. Hormonal responses

4.1.1. Growth hormone

4.1.2. Testosterone

4.1.3. Cortisol

4.1.4. Insulin‐like growth factor‐1

4.1.5. Vascular endothelial growth factor

4.1.6. Noradrenaline

4.1.7. Ghrelin, sex hormone binding globulin, androstenedione, β‐endorphine, and irisin

4.2. Immune responses

4.2.1. Iinterleukin‐6

4.2.2. Interleukin‐15

4.2.3. Creatine phosphokinase

4.2.4. 2‐Arachidonoylglycerol, decorin, superoxide dismutase, and catalase

4.3. Oxidative stress responses

4.3.1. Nitric oxide

4.3.2. Protein carbonyls

4.3.3. Reactive oxygen species, neuronal nitric oxide synthase, inducible nitric oxide, endothelial nitric oxide synthase, and glutathione

4.4. Subgroup analyses

4.5. Effects of BFR cuff pressure on acute hormonal, immune, and oxidative stress responses

4.6. Acute versus long‐term training‐induced hormonal, immune, and oxidative stress responses

4.7. Timing of physiological responses in initial, intermediate, and late post‐exercise time intervals

5. LIMITATIONS

6. CONCLUSION AND PERSPECTIVES

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

Supporting information

ACKNOWLEDGMENTS

DATA AVAILABILITY STATEMENT

REFERENCES

Associated Data