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Journal of Exercise Science and Fitness logoLink to Journal of Exercise Science and Fitness
. 2023 Nov 23;22(1):51–58. doi: 10.1016/j.jesf.2023.11.002

Acute effect of exercise intensity on circulating FGF-21, FSTL-1, cathepsin B, and BDNF in young men

Minje Ji a, Chaeeun Cho a, Sewon Lee b,c,d,∗
PMCID: PMC10698539  PMID: 38074189

Abstract

Background/objectives

Exercise intensity is potentially an important regulator of various exerkines secretion, but the optimal exercise intensity to increase and sustain exerkines levels, including FGF-21, FSTL-1, cathepsin B, and BDNF in humans, has not yet been fully elucidated. This study aimed to examine the circulating levels of FGF-21, FSTL-1, cathepsin B, and BDNF according to the exercise intensity.

Methods

Nine young men (24.0 ± 0.4 years old) performed 4 different experimental sessions at 1-week intervals: 1) a control session (CTRL; no exercise); 2) moderate-intensity continuous exercise (MICE, 55% HRR); 3) vigorous-intensity continuous exercise (VICE, 85% HRR); and 4) high-intensity interval exercise (HIIE, 4 repetitions of a 30-s of “all out” cycling workout followed by a 4-min recovery). Blood samples were collected at 4 different time points (pre-exercise, immediately post-exercise, 30 min post-exercise, and 90 min post-exercise).

Results

Serum FGF-21, FSTL-1, cathepsin B, and BDNF were higher in HIIE than in CTRL immediately post-exercise, and FSTL-1, cathepsin B, and BDNF were higher in HIIE than in MICE immediately post-exercise (P < 0.05). The AUC for FGF-21, FSTL-1, and BDNF was higher in HIIE than in CTRL, and the AUC for FGF-21 and BDNF was higher in HIIE than in MICE (P < 0.05). Furthermore, the change in blood lactate was positively correlated with the changes in all exerkines.

Conclusions

This study demonstrates that acute HIIE effectively increases serum FGF-21, FSTL-1, cathepsin B, and BDNF compared to MICE. Therefore, the secretion of exerkines, including FGF-21, FSTL-1, cathepsin B, and BDNF may be exercise intensity-dependent.

Keywords: Exerkine, Lactate, HIIE, Wingate test, Myokine

1. Introduction

The recent COVID-19 pandemic has exacerbated the prevalence rate of reduced physical activity and increased sedentary lifestyles.1,2 Lack of physical activity is the pandemic, a leading cause of death worldwide.3 The World Health Organization (WHO) estimates that approximately 500 million additional people will develop non-communicable diseases attributable to physical inactivity, between 2020 and 2030.4 Indeed, physical inactivity is attributed to cardiometabolic diseases, Alzheimer's disease, and dementia, which in turn shortens healthy life years and increases health care costs and mortality risk.5, 6, 7 Conversely, exercise is an effective non-pharmacological intervention for the prevention and amelioration of cardiometabolic and neurological diseases via the release of bioactive hormones, which are the so-called exerkines, including myokines (skeletal muscle), hepatokines (liver), adipokines (adipose tissue), and cardiokines (heart).7, 8, 9 Exercise-induced exerkines play a positive role in various tissues and organ systems through endocrine, autocrine, and/or paracrine mechanisms.9,10

Various physiological functions and organ systems, including the cardiometabolic system and nervous system, are influenced by exercise-derived exerkines.9 For example, fibroblast growth factor-21 (FGF-21), primarily secreted in the liver, adipose tissue, and skeletal muscle, is one of the exerkines which regulate glucose and lipid metabolism via decreasing fasted glucose, triglycerides, and low-density lipoprotein cholesterol (LDL-C), increasing glucose uptake and high-density lipoprotein cholesterol (HDL-C), and improving insulin sensitivity.11, 12, 13, 14, 15, 16 FGF-21 also enhances energy expenditure and stimulates white adipose tissue browning.15,17 Another exerkine, follistatin-like protein 1 (FSTL-1), predominantly secreted in skeletal muscle and heart, ameliorates endothelial cell function and stimulates revascularization in ischemic tissue via activation of the endothelial nitric oxide synthase (eNOS) signaling mechanism.8,18 Thus, it has been suggested that exercise-induced FSTL-1 may inhibit the progression of atherosclerosis by ameliorating endothelial dysfunction and arterial stiffness.19,20 In addition, other exerkines including brain-derived neurotrophic factor (BDNF) and cathepsin B have been suggested to improve neurological function. Exercise-induced BDNF plays a pivotal role in not only the enhanced lipid oxidation but also neurogenesis and synaptic plasticity.21,22 Cathepsin B is positively associated with aerobic fitness and hippocampus-dependent memory function.23 Furthermore, cathepsin B has been suggested to potentially improve neuroprotective functions with decreased amyloidogenic properties.24,25 Interestingly, cathepsin B is considered to be able to cross the blood-brain barrier (BBB) and regulate BDNF expression through this exerkine.23 Taken together, the secretion of exerkines in various organs may be an attractive and potential therapeutic target to promote cardiometabolic and neurological health.

However, the most effective exercise regimen (e.g., exercise intensity) to increase the secretion of exerkines is still unclear. While previous studies have shown that several mechanisms associated with exercise intensity and exercise type may link as regulators of exerkines secretion, this study was particularly interested in lactate which increases with an exercise intensity-dependent manner.26,27 While several studies have indicated that high-intensity exercise promotes more exerkines secretion than moderate-intensity exercise,28,29 another previous study has shown no difference in exerkine levels depending on exercise intensity.30 Exercise intensity is potentially an important regulator of various exerkines secretion, but in humans, the optimal exercise intensity (moderate vs. high intensity, and submaximal continuous vs. supramaximal interval) that increases and sustains exerkines levels including FGF-21, FSTL-1, cathepsin B, and BDNF has not yet been fully elucidated. Therefore, this study aimed 1) to examine the circulating levels of FGF-21, FSTL-1, cathepsin B, and BDNF according to the intensity of exercise using a bicycle ergometer, 2) to examine the changing trend of each exerkine at the different time points (pre-exercise, immediately post-exercise, 30 min post-exercise, and 90 min post-exercise), and 3) to investigate the correlation between exerkine secretion and lactate, which is utilized as a mediator for exercise intensity.

2. Methods

2.1. Participants

Ten young men aged 18-29, non-smokers and healthy determined by the Physical Activity Readiness Questionnaire (PAR-Q+) voluntarily participated in this study. Exclusion criteria included smokers or those who quit smoking within 5 years, patients with any musculoskeletal disorders, kidney diseases, neurological diseases, and cardiometabolic diseases including hypertension, metabolic syndrome, and type 2 diabetes. All participants were physically active (less than or equal to three sessions per week) as assessed by International Physical Activity Questionnaires (IPAQ) and did not participate in a systemic exercise training program for at least 6 months prior to participation in this study. Participants in the experiment were instructed to restrict intake of dietary supplements at the time of the study. Among the ten participants, one participant's data was excluded from the analysis because one participant did not adhere control (timing of blood collection and recording energy intake) due to personal reasons. Therefore, the data of 9 participants were finally analyzed. This study was approved by the Institutional Review Board at Incheon National University (permission# 7007971-202104-010A) prior to the start of the study. Experimental details including research procedures and associated potential risks were explained to all participants and participants who agreed to participate in the study voluntarily signed a written consent form.

2.2. Experimental design

The experimental procedure has been designed and modified based on previous research conducted by Hashim Islam et al.27 Participants visited the laboratory once a week on the same day and at the same time for 5 weeks. A week before the first experimental session, participants performed a familiarization and pre-experimental session to measure maximum oxygen consumption (VO2max) and baseline clinical characteristics including PAR-Q+, IPAQ, body composition, blood pressure, arterial stiffness, lipid and glucose profiles, and grip strength. All participants performed 4 different experimental sessions at 1-week intervals, and the order of exercise sessions was randomized using a counterbalanced Latin square design.27 The experimental sessions consisted of the following 4 parts: 1) a control session (CTRL; no exercise); 2) moderate-intensity continuous exercise (MICE, 55% of heart rate reserve [HRR]); 3) vigorous-intensity continuous exercise (VICE, 85% HRR); and 4) high-intensity interval exercise (HIIE, four 30 s bouts of “all-out” cycling workout [Wingate test] interspersed with 4 min recovery). All experimental sessions were performed on the bicycle ergometer-based exercise (recumbent ergometer or Wingate test). Whole blood samples were collected intravenously by a registered nurse at 4 different time points (pre-exercise, immediately post-exercise, 30 min post-exercise, and 90 min post-exercise) during all experimental periods. Participants were instructed to restrict strenuous physical activities, caffeine, and alcohol for at least 24 h, to maintain the fasted state for at least 10 h, and to sleep for at least 7 h before a pre-experimental session and before all experimental sessions. Participants’ energy intake was recorded over 3-day (previous day, day, and next day) using a calorie counter app, FatSecret (Secret industries Pty Ltd, Australia), and participants were instructed to have similar dietary intake for all 3 days in the pre-experiment and in all experimental sessions. All experiments were performed in a laboratory where temperature (21-23 °C) and humidity (40-50%) were maintained under stable conditions.

2.3. Familiarization & pre-experimental session

All participants completed a pre-experimental session including baseline clinical characteristics, measurement of VO2max, and familiarization with the exercise protocol 1 week prior to the first experimental session. Participants visited the laboratory after an overnight fast for at least 10 h. Upon arrival, PAR-Q+, IPAQ, body composition assessed by dual energy X-ray absorptiometry (Lunar prodigy, GE, USA), blood pressure (Accuniq BP850, Jawon Medical, South Korea), peripheral arterial stiffness (VP-100 plus, Omron, Japan), circulatory levels of lipid and glucose profiles (Cholestech LDX, Alere, Norway), and grip strength assessed by hand dynamometer (Digital hydraulic hand dynamometer 300 lbs, Baseline®, USA) were sequentially measured. Participants then were given a standardized test meal (7 kcal/kg body weight) consisting of a water (provided ad libitum throughout the session) and energy bars (50% carbohydrates, 15% protein, 25% fat, 10% fiber). Participants consumed a standardized test meal provided for 15 min, then sat down and relaxed for 30 min. After rest, participants underwent graded exercise test on a recumbent ergometer (Corival recumbent cpet, Lode, Netherlands) to exhaustion to determine VO2max and analyzed using a metabolic analyzer (Quark CPET, USA). During the graded exercise test, the oxygen uptake (VO2), carbon dioxide production (VCO2), pulmonary ventilation (VE), and respiratory exchange ratio (RER) were continuously measured for breath-by-breath through a metabolic analyzer. For accurate gas and heart rate (HR) measurement, participants wore a tightly sealed facemask connected to an airflow sensor, and the HR monitor (H7 heart rate sensor, Polar Electro, Finland) was worn tightly on the chest.

The VO2max test consisted of a 5-min warm-up (3 min of dynamic stretching and 2 min of 0 W cycling) followed by cycling at a pedaling rate (60 rpm) throughout the test. The initial work rate was 50 W for 2 min, thereafter the work rate was increased by 30 W every 2 min in a constant and continuous manner until volitional exhaustion was achieved. VO2max was determined when either the greatest 30 s average at which VO2 values plateaued (increase <1.35 ml kg−1 min−1) despite the increase in work rate, or two of the following criteria were met: 1) RER >1.15; 2) maximal HR (within 10 bpm of age-predicted maximum [220 - age]) and/or; 3) a rating of perceived exertion (RPE, scoring 6-20) of 19 or 20. One participant failed to meet the criteria, so VO2max and HRmax were used as VO2peak and HRpeak, respectively. After a 5-min cooldown and a 20-min rest period, the grade required to elicit appropriate workloads for the MICE (55% HRR) and VICE (85% HRR) sessions were determined.

2.4. Experimental sessions

Participants arrived at the laboratory the next day morning after an overnight fast (at least 10 h) to complete the experimental session. Upon arrival, participants received a standardized test meal (equivalent to the familiarization session) consisting of an appropriate amount (g) of energy bar (50% carbohydrates, 15% protein, 25% fat, 10% fiber) and water. After a 15-min meal and 30-min rest, participants performed an exercise protocol consisting of a 5-min standardized warm-up (3 min of dynamic stretching and 2 min of 50 W cycling), followed by a 30-min main exercise protocol (MICE or VICE), and a 5-min standardized cooldown sequentially. Participants in the MICE and VICE sessions performed the main exercise protocol with a recumbent ergometer in the same way they performed in the graded exercise test. The pedaling rate for MICE and VICE sessions was instructed to be maintained at 50-70 rpm. The MICE and VICE protocols were performed on a recumbent ergometer and consisted of 30 min of continuous cycling at target intensities of 55% and 85% HRR, respectively. The intensities of exercise were determined as moderate exercise with an HRR intensity of about 40%–59%, and vigorous exercise with an HRR intensity of about 60%–89% according to the guidelines of the American College of Sports Medicine (ACSM).31

Participants in the HIIE session performed the Wingate test (894E model, Monark, Vansbro, Sweden), known as the traditional anaerobic power test, against a resistance load of 7.5% body weight. To match exercise protocol duration between exercise interventions, HIIE sessions were allocated an additional 12 min of rest before warm-up followed by 18 min of HIIE exercise protocol (4 repetitions of a 30-s of “all out” cycling workout followed by a 4-min recovery). HR was measured continuously throughout HIIE protocols and RPE was measured 4 times after the end of every 4 “all out” cycling workout.

Upon completion of each exercise protocol, participants rested comfortably for an additional 90 min at which time a blood collection was conducted by a registered nurse. The experimental protocol within the CTRL sessions proceeded with comfortable rest at the time allotted to the exercise protocol, followed by an additional 90-min rest period as in other exercise sessions. During rests, participants were instructed to restrict physical activity and exciting video. The study flow chart of experimental sessions was shown in Fig. 1.

Fig. 1.

Fig. 1

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Schematic flow chart of the experiment sessions.

2.5. Blood collection and serum analysis

Venous blood samples (12 ml each) at 4 different points were collected by a nurse from the antecubital vein in a seated position, and the collected blood was dispensed into 3 separate vacutainer tubes (4 ml of blood each). To measure blood lactate concentration, 25 μl of blood was withdrawn using a transfer pipette from one of the vacutainer tubes and circulating lactate levels were measured using an accutrend plus (Mannheim, Germany). The collected blood samples were coagulated for 30 min at room temperature and then centrifuged at 3000g for 15 min at 4 °C to separate serum. Serum samples were stored in a −80 °C cryogenic freezer until further analysis. Serum concentrations of FGF-21 (R&D System, USA, Catalogue No: DF2100), FSTL-1 (CUSABIO, USA, Catalogue No: CSB-E13516h), cathepsin B (Abcam, USA, Catalogue No: ab119584), and BDNF (R&D System, USA, Catalogue No: DBD00) were measured using enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer's instructions. Briefly, standards, serum samples, washing buffer, and assay buffer were prepared. Pre-coated 96 wells plates were used and read using a plate reader at 450 nm. All serum samples were measured in duplicate, and the results obtained were calculated using the best-fit standard curve. The intra-assay coefficients of variation for FGF-21, FSTL-1, cathepsin B, and BDNF were less than 10% (4.7%, 9.4%, 6.5%, and 9.2%, respectively). Similarly, the inter-assay coefficients of variation for FGF-21, FSTL-1, cathepsin B, and BDNF were less than 10% (9.1%, 5.9%, 9.8%, and 8.8%, respectively).

2.6. Statistical analysis

All statistical analyses were performed using GraphPad Prism (version 9.0, GraphPad Software, USA), and figures were also prepared using GraphPad Prism. All data were presented as a mean ± SEM and the normality of distribution for variables was evaluated using the Shapiro-Wilk test. Comparison of blood variable responses among 4 sessions over time was performed by repeated measures two-way ANOVA (4 ⅹ 4; session ⅹ time). A Greenhouse–Geisser correction was applied if sphericity was violated and post hoc analysis was performed with Fisher's LSD test. The area under the curve (AUC) for blood variables fluctuations across experiment sessions (trapezoid rule) was calculated using the alteration in each variable relative to baseline. A one-way ANOVA with repeated measurements was performed to compare blood variable AUC values across sessions. In the case of variables not following the normality, Friedman's test was performed. The relationship between blood variables and lactate was performed using Spearman correlation analysis. The statistical significance level was set at P < 0.05.

3. Results

3.1. Basic clinical characteristics of participants

The basic clinical characteristics of the 9 participants were as shown in Table 1. Participants were a mean age of 24.0 ± 0.4 years, and had height of 174.6 ± 2.0 cm, weight of 77.1 ± 2.8 kg, BMI of 25.2 ± 0.7 kg/m2. Furthermore, participants had mean lean mass of 58.5 ± 1.4 kg, fat mass of 15.8 ± 2.0 kg, and VO2 peak of 36.1 ± 1.5 ml kg−1 min−1. There were no differences (P = 0.448) in mean energy intake for a 3-day period (previous day, day, and next day) in all sessions.

Table 1.

Basic clinical characteristics of study participants.

Variables Participants (n = 9)
Age (years) 24.0 ± 0.4
Height (cm) 174.6 ± 2.0
Weight (kg) 77.1 ± 2.8
BMI (kg/m2) 25.2 ± 0.7
Lean mass (kg) 58.5 ± 1.4
Fat mass (kg) 15.8 ± 2.0
baPWV (cm/s) 1194.2 ± 34.4
SBP (mmHg) 119.8 ± 2.5
DBP (mmHg) 67.7 ± 2.2
TC (mg/dL) 167.3 ± 8.7
TG (mg/dL) 78.1 ± 10.9
HDL-C (mg/dL) 58.6 ± 2.9
LDL-C (mg/dL) 83.0 ± 11.3
FG (mg/dL) 90.7 ± 1.1
HbA1c (%) 5.1 ± 0.1
Hand grip strength (kg) 51.5 ± 1.7
Hand grip strength (kg/m2) 17.0 ± 0.8
VO2 peak 36.1 ± 1.5
HR peak (bpm) 182.2 ± 2.3
RPE peak 19.2 ± 0.2
WR peak (W) 246.7 ± 7.3
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Values are shown as mean ± SEM. Abbreviations: baPWV = brachial-ankle pulse wave velocity; BMI = body mass index; DBP = diastolic blood pressure; FG = fasting glucose; HbA1c = Hemoglobin A1c; HDL-C = high density lipoprotein cholesterol; HR = heart rate; LDL-C = low density lipoprotein cholesterol; RPE = rate of perceived exertion; SBP = systolic blood pressure; TC = Total cholesterol; TG = Triglyceride; VO2 peak = peak oxygen uptake; WR = work rate.

3.2. Verification of exercise intensity

All participants completed exercise sessions at the prescribed intensities. In exercise protocols, whether participants properly performed the various exercise intensities (MICE, VICE, and HIIE) was assessed through RPE and HR. At the end of exercise, RPE was the highest in HIIE (19.8 ± 0.2, P < 0.001 vs. MICE, P < 0.001 vs. VICE), and RPE in VICE (16.8 ± 0.4) was higher (P < 0.001) than that in MICE (12.7 ± 0.5). Similarly, HR was the highest in HIIE (173.6 ± 3.2 bpm, P < 0.001 vs. MICE, P = 0.002 vs. VICE), and HR in VICE (159.7 ± 1.2 bpm) was higher (P < 0.001) than that in MICE (125.3 ± 1.2 bpm). The exercise intensities (MICE, VICE, and HIIE) of RPE and HR were in the range of moderate, vigorous, and near-maximal to maximal exercise intensities according to the guidelines of the ACSM.31 Peak power output (PPO) during HIIE, averaged over all 4 “all out” maximal efforts, was 785.7 ± 33.1 W, and relative PPO (W/kg) during HIIE was 10.2 ± 0.4 W/kg (Data not shown)

In addition, in this study, lactate was used as a mediator of exercise intensity. There was no difference (P = 0.630) in absolute lactate concentrations at baseline level among the sessions (CTRL: 2.2 ± 0.1 mmol/L; MICE: 2.1 ± 0.1 mmol/L; VICE: 2.3 ± 0.2 mmol/L; HIIE: 2.3 ± 0.1 mmol/L). Lactate was highest in the HIIE session than all other sessions immediately post-exercise (P < 0.001), and lactate was significantly higher in the VICE session than in the MICE and CTRL sessions at this time point (both P < 0.001; Fig. 2). Lactate remained highest at 30 min and 90 min post-exercise in the HIIE session than in all other sessions (P < 0.001; Fig. 2), whereas lactate in the VICE session returned to similar levels to baseline at 30 min post-exercise (P > 0.05).

Fig. 2.

Fig. 2

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Changes in lactate across 4 exercise sessions and 4 time points relative to baseline. *,#,&HIIE significantly different from CTRL, MICE, and VICE, respectively, P < 0.05. $,†VICE significantly different from CTRL and MICE, respectively, P < 0.05. Values are shown as mean ± SEM.

3.3. Fibroblast growth Factor-21

Absolute serum FGF-21 levels did not differ (P = 0.706) among the sessions at baseline (CTRL: 73.7 ± 10.0 pg/mL; MICE: 96.4 ± 42.7 pg/mL; VICE: 70.9 ± 9.7 pg/mL; HIIE: 67.9 ± 16.6 pg/mL). Serum FGF-21 was significantly higher in the HIIE session than in the CTRL session immediately post-exercise (P = 0.024; Fig. 3A). In addition, FGF-21 was significantly higher in the VICE and HIIE sessions than in the CTRL session at 30 min post-exercise (P = 0.009 and P = 0.025, respectively; Fig. 3A). FGF-21 returned to levels comparable to baseline at 90 min post-exercise (P > 0.05). The AUC for FGF-21 was significantly higher in the HIIE session than in the CTRL and MICE sessions (P = 0.001 and P = 0.006, respectively; Fig. 3B). Additionally, the AUC for FGF-21 was significantly higher in the VICE session than in the CTRL session (P = 0.018; Fig. 3B). Although the AUC for FGF-21 tended to be higher in the VICE session than in the MICE session (P = 0.068), the difference was not statistically significant.

Fig. 3.

Fig. 3

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Changes in FGF-21 across 4 exercise sessions and 4 time points relative to baseline (A). AUC for FGF-21 across 4 time points in 4 exercise sessions relative to baseline (B). *,#HIIE significantly different from CTRL and MICE, respectively, P < 0.05. $VICE significantly different from CTRL, P < 0.05. Values are shown as mean ± SEM.

3.4. Follistatin-like protein 1

Absolute serum FSTL-1 levels did not differ (P = 0.644) among the sessions at baseline (CTRL: 2.6 ± 0.8 ng/mL; MICE: 2.4 ± 0.7 ng/mL; VICE: 1.7 ± 0.8 ng/mL; HIIE: 1.8 ± 1.0 ng/mL). Serum FSTL-1 was significantly higher in the HIIE session than in the CTRL and MICE sessions immediately post-exercise (P = 0.016 and P = 0.019, respectively; Fig. 4A). FSTL-1 returned to levels comparable to baseline at 30 min and 90 min post-exercise (P > 0.05). The AUC for FSTL-1 was significantly higher in the HIIE session than in the CTRL session (P = 0.049; Fig. 4B), with a tendency toward higher in the VICE session than in the CTRL session (P = 0.079), but the difference was not statistically significant.

Fig. 4.

Fig. 4

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Changes in FSTL-1 across 4 exercise sessions and 4 time points relative to baseline (A). AUC for FSTL-1 across 4 time points in 4 exercise sessions relative to baseline (B). *,#HIIE significantly different from CTRL and MICE, respectively, P < 0.05. Values are shown as mean ± SEM.

3.5. Cathepsin B

Absolute serum cathepsin B levels did not differ (P = 0.769) among the sessions at baseline (CTRL: 541.0 ± 199.4 pg/mL; MICE: 679.7 ± 168.9 pg/mL; VICE: 809.5 ± 372.1 pg/mL; HIIE: 903.8 ± 288.8 pg/mL). Serum cathepsin B was significantly higher in the HIIE session than in the CTRL and MICE sessions immediately post-exercise (P = 0.005 and P = 0.001, respectively; Fig. 5A), with a tendency toward higher in the HIIE session than in the VICE session (P = 0.095), but the difference was not statistically significant. Cathepsin B returned to levels comparable to baseline at 30 min and 90 min post-exercise (P > 0.05). Although the AUC for cathepsin B tended to be higher in the HIIE session than in the MICE session (P = 0.068; Fig. 5B), the difference was not statistically significant.

Fig. 5.

Fig. 5

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Changes in cathepsin B across 4 exercise sessions and 4 time points relative to baseline (A). AUC for cathepsin B across 4 time points in 4 exercise sessions relative to baseline (B). *,#HIIE significantly different from CTRL, MICE, and VICE, respectively, P < 0.05. Values are shown as mean ± SEM.

3.6. Brain-derived neurotrophic factor

Absolute serum BDNF levels did not differ (P = 0.150) among the sessions at baseline (CTRL: 22845.5 ± 2992.1 pg/mL; MICE: 25385.8 ± 3309.7 pg/mL; VICE: 21141.9 ± 2676.7 pg/mL; HIIE: 20972.6 ± 2199.7 pg/mL). Serum BDNF was significantly higher in the HIIE session than in the CTRL, MICE, and VICE sessions immediately post-exercise (P < 0.001, P = 0.001, and P = 0.0214, respectively; Fig. 6A). In addition, BDNF was significantly higher in the HIIE session than in the MICE and VICE sessions at 30 min post-exercise (P = 0.027 and P = 0.002, respectively; Fig. 6A), with a tendency toward higher in the HIIE session than in the CTRL session (P = 0.07), but the difference was not statistically significant. BDNF returned to levels comparable to baseline at 90 min post-exercise (P > 0.05). The AUC for BDNF was significantly higher in the HIIE session than in the CTRL and MICE sessions (P = 0.006 and P = 0.011, respectively; Fig. 6B).

Fig. 6.

Fig. 6

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Changes in BDNF across 4 exercise sessions and 4 time points relative to baseline (A). AUC for BDNF across 4 time points in 4 exercise sessions relative to baseline (B). *,#,&HIIE significantly different from CTRL, MICE, and VICE, respectively, P < 0.05. Values are shown as mean ± SEM.

3.7. Correlation analysis

Previous studies have shown that increased lactate levels stimulate BDNF expression in an experimental mouse model.32 In addition, the changes in blood lactate after exercise positively correlate with the changes in BDNF in humans.28 However, the relationship between changes in other exerkines and lactate after exercise remains largely unknown. Therefore, in this study, a correlation analysis was performed between changes in exerkines and lactate immediately post-exercise relative to baseline. The change in blood lactate was positively correlated with the changes in FGF-21 (r = 0.457, P = 0.005; Fig. 7A), FSTL-1 (r = 0.476, P = 0.003; Fig. 7B), cathepsin B (r = 0.507, P = 0.002; Fig. 7C), and BDNF (r = 0.752, P < 0.001; Fig. 7D).

Fig. 7.

Fig. 7

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Correlation analysis between changes in FGF-21 (A), FSTL-1 (B), cathepsin B (C), and BDNF (D) and change in lactate.

4. Discussion

This study investigated the effects of acute exercise according to intensity on circulating exerkines levels. To the best of our knowledge, the present study is the first to examine changes in serum exerkines response, especially FSTL-1 and cathepsin B, to intensity-dependent acute effects of bicycle ergometer-based exercise. This study showed that HIIE was more effective in increasing serum FGF-21, FSTL-1, cathepsin B, and BDNF. Additionally, increases in FGF-21, FSTL-1, cathepsin B, and BDNF were strongly associated with increases in lactate immediately post-exercise.

FGF-21, a member of the FGF superfamily subgroup, is released under stress conditions such as exercise, fasting, mitochondrial myopathy.11,33, 34, 35, 36 FGF-21 has been proposed as a potential therapeutic target for metabolic dysfunction such as obesity, insulin resistance, and type 2 diabetes.15,37 Interestingly, in this study, FGF-21 was increased in HIIE immediately post-exercise and increased in HIIE and VICE at 30 min post-exercise. In addition, the AUC for FGF-21 was significantly higher in the HIIE session than in the CTRL and MICE sessions. Similarly, a previous study has shown that serum FGF-21 levels were higher during high-intensity aerobic exercise than moderate-intensity aerobic exercise in humans.34 In this study, the change in FGF-21 was positively associated with the change in lactate. A previous study showed that lactate induced up-regulation of FGF-21 in adipocytes through p38 mitogen-activated protein kinase (MAPK) activation.38 Considering these findings, increased FGF-21 levels implicate a dependence on exercise intensity and lactate levels. Although these findings indicated that VICE and HIIE effectively increased FGF-21 levels, another previous study showed that increases in FGF-21 levels tended to be higher after resistance exercise than after running-based HIIE.39 Therefore, follow-up studies on the FGF-21 response according to resistance exercise intensity and exercise type (aerobic vs. resistance) are needed.

FSTL-1 is a relatively new and little-known exerkine. To our knowledge, the acute effects of intensity-dependent exercise on FSTL-1 response have not been investigated both in experimental animal models and in humans. FSTL-1 has been suggested to have beneficial effects on metabolic homeostasis and the cardiovascular system.8,18,40 This study showed an increased FSTL-1 response in HIIE, but FSTL-1 levels did not increase after MICE. The MICE protocols (55% HRR) in this study may be insufficient to stimulate FSTL-1 secretion to increase circulating levels. In contrast, previous studies indicated that increased FSTL-1 levels after acute endurance exercise in rat serum and after 60 min of moderate-intensity aerobic exercise (70% VO2max) in human serum.41,42 These conflicting results may be due to differences in study methods, such as duration of continuous exercise, animal vs. human model, and %VO2max vs. %HRR. However, the increased FSTL-1 levels after HIIE was consistent with a previous result using a similar protocol which 4 repetitions of 30-s of “all out” cycling workout followed by a 4-min recovery.43 Furthermore, this study showed that FSTL-1 was a positive correlation with lactate. These interesting findings indicate that exercise protocols that elicit supramaximal intensity stimulate the greatest FSTL-1 response and the increase in FSTL-1 may be related to lactate.

Exercise directly affects muscle-brain crosstalk through exerkines, such as cathepsin B and BDNF, both of which are responsible for regulating brain function.44 Another interesting finding of this study was increased both cathepsin B and BDNF in HIIE. In a previous study, aerobic exercise led to an increase in plasma cathepsin B in mice, rhesus monkeys, and humans.23 Furthermore, increased cathepsin B in mice, which applied exogenous cathepsin B to hippocampal progenitor cells, enhances the BDNF expression in the hippocampus.23 In contrast, cathepsin B knockout mice were resistant to the effect of exercise as regards hippocampal neurogenesis and ameliorated memory.23 Given this previous finding, increased BDNF in this study may be related to increased cathepsin B. BDNF can be affected by blood lactate levels and a previous study reported that lactate infusion in humans increased BDNF plasma levels at rest.45 Additionally, increased lactate levels during exercise in mice induced hippocampal BDNF expression via a Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α)/fibronectin type III domain-containing protein 5 (FNDC5) signaling pathway.32 This lactate-mediated increase in BDNF expression and related-signaling was associated with improved memory and learning.32 This study shows that BDNF levels in HIIE were significantly higher than all other sessions (CTRL, MICE, and VICE) immediately post-exercise, and changes in BDNF were closely related to changes in lactate. These findings suggest that changes in BDNF response after exercise may be influenced by lactate and cathepsin B, and these findings indicate that BDNF levels increase with increasing exercise intensity.

In this study, HIIE increased in all exerkines (FGF-21, FSTL-1, cathepsin B, and BDNF) levels immediately post-exercise, suggesting that an exercise regimen superior to elevate exerkines levels is associated with high-intensity and supramaximal interval exercise rather than moderate-intensity and submaximal continuous exercise. HIIE is known to be an effective exercise for improving cardiometabolic risk factors and cognitive function.46, 47, 48, 49, 50, 51 Exerkines may have contributed to these beneficial effects of HIIE. Interestingly, this study showed that the exerkines may be molecules with a short half-life since exerkines returned to baseline levels at 90 min post-exercise in all exercise sessions. On the other hand, a previous study has shown that FGF-21 levels increased even after 90 min post-exercise.39 Therefore, follow-up studies will need to investigate the exerkines response with the longer time points so that it can help understand the sustainability of the beneficial effect of exercise and establish an exercise frequency that can effectively induce an increase in exerkines.

This study has a few limitations. First, since this study targeted healthy and active young men, it is difficult to generalize these results to other populations such as the elderly and those with special diseases. Second, this study had a small sample size and no comparisons with other population groups. Further studies are required with large sample sizes and comparisons between different population groups to confirm our findings. Third, this study investigated the exerkines response according to the acute exercise intensity, but additional studies on exerkines response according to various exercise types or chronic exercise are needed. Lastly, we analyzed serum levels of various exerkines according to exercise intensity, but not mRNA and protein levels. Therefore, future studies need to investigate exerkines-related signaling pathways in more detail, including mRNA and protein levels via muscle or fat biopsies.

5. Conclusions

This study shows that acute HIIE effectively increases circulating serum FGF-21, FSTL-1, cathepsin B, and BDNF levels compared to CTRL and MICE. These results suggest that HIIE is a more suitable exercise method to increase specific exerkines levels than MICE. In addition, changes in FGF-21, FSTL-1, cathepsin B, and BDNF were associated with changes in lactate immediately post-exercise. These findings support the possible involvement of lactate in the specific exerkines response to acute exercise. Therefore, we suggest that the secretion of exerkines, including FGF-21, FSTL-1, cathepsin B, and BDNF may be exercise intensity-dependent.

Author statement

Minje Ji: Writing – Original Draft preparation, Conceptualization, Data curation, Visualization, Formal analysis, Methodology.

Chaeeun Cho: Data curation, Formal analysis, Methodology.

Sewon Lee: Conceptualization, Project administration, Funding acquisition, Writing-Reviewing and Editing.

Funding

This study was supported by Incheon National University Research Grant in 2022.

Ethics approval

This study was approved by the Institutional Review Board at Incheon National University (permission# 7007971-202104-010A).

Declaration of competing interest

The authors declare that they have no competing interests.

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