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The Journal of Spinal Cord Medicine logoLink to The Journal of Spinal Cord Medicine
. 2020 Apr 16;44(6):920–930. doi: 10.1080/10790268.2020.1752976

Effects of intensity-matched exercise at different intensities on inflammatory responses in able-bodied and spinal cord injured individuals

Eduardo da Silva Alves 1,2,3,✉, Ronaldo Vagner Thomatiele dos Santos 2, Fábio Santos de Lira 4, Alexandre Aparecido Almeida 5, Kate Edwards 6, Mateus Benvenutti 7, Sergio Tufik 2, Marco Túlio De Mello 3,8
PMCID: PMC8725751  PMID: 32298225

Abstract

Objective: To compare the effects of intensity-matched acute exercise at different intensities on proinflammatory and anti-inflammatory cytokines between able-bodied (AB) and spinal cord injured (SCI) individuals.

Design: Non-Randomized Controlled Trial.

Setting: Community settings in São Paulo – Brazil.

Participants: Eight AB and nine SCI paraplegic.

Interventions: Participants underwent three exercise sessions at different relative intensities: at ventilatory threshold 1 intensity (VT1), 15% below VT1, and 15% above VT1. Similar energy expenditures were established from exercises with different intensities for each volunteer. The AB group was tested on a conventional treadmill, whereas the SCI group was tested on a treadmill adapted for wheelchair use. Blood samples were collected at baseline, immediately after, and 30 min after the exercise sessions.

Outcome measures: Interleukin 1 receptor antagonist, interleukin 1 beta, interleukin 2, interleukin 4, interleukin 6, interleukin 10 and tumoral necrosis factor alpha were measured.

Results: When groups were compared, interleukin – 2 was found higher, whereas interleukin – 4 and interleukin – 10 were found lower in the SCI group at all collection times in the three exercise intensities (all P < 0.05). Interleukin – 1 receptor antagonist was found higher immediately after exercise at VT1, 15% above VT1 and 30 min after 15% below VT1 in the AB group (all P < 0.05). In the AB group, an increase in interleukin – 6 immediately after the exercise at VT1 compared with baseline was found (P = 0.01).

Conclusion: Individuals with SCI may have to perform physical exercise at a higher volume or energy expenditure than AB individuals to obtain similar anti-inflammatory benefits of acute exercise.

Trial registration: Uniform Trial Number identifier: U1111-1232-8142.

Keywords: Spinal cord injuries, Inflammation, Acute physical exercise, Rehabilitation, Cytokines

Introduction

Spinal cord injury (SCI) is a medical condition in which neurological dysfunction leads to important physiological and functional limitations.1 Serum levels of inflammatory markers such as cytokines have been shown to be higher in individuals with SCI.2,3 In addition, physical inactivity, obesity and marked deconditioning (low fitness level) are highly prevalent in these individuals.4–6 The combination of these factors may explain the increased risk for cardiovascular disease (CVD) in the SCI population.7–9

Regular physical activity and exercise are known for their anti-inflammatory effects in many diseases, especially CVD. Large populations studies have consistently shown inverse relationships between exercise participation and all cause, and CVD, mortality in able-bodied (AB) individuals.10,11 In people with SCI, a recent meta-analysis has shown that physical activity and exercise may improve systemic markers of low-grade inflammation, particularly interleukin – 6 (IL-6) and C-reactive protein.9,12

A single bout of exercise increases the circulating concentration of IL-6, derived from contracting myocytes.13 This increase stimulates an anti-inflammatory cascade including increases in interleukin receptor antagonist 1 (IL1-ra) and interleukin – 10 (IL-10).14,15 As well as promoting an anti-inflammatory effect, IL-6 released from muscles is associated with many positive metabolic effects, such as improvement in insulin sensitivity and increase in lipolysis.14,15 Therefore, by repetition of the acute induction of an anti-inflammatory environment, repeated bouts of exercise may be beneficial for improving an individuaĺs inflammatory status in the long term, thus reducing morbidity and mortality from chronic diseases.13

The major source of circulating IL-6 during exercise is the contracting muscle, which explicates the positive relationship between exercise volume and intensity on circulating plasma IL-6 concentration.15,16 The amount of muscle mass engaged during exercise may similarly influence cytokine concentrations, but studies are still inconclusive.12,15,17,18 For example, the decreased amount and function of muscle mass in individuals with SCI would be expected to limit the IL-6 response and therefore the potential anti-inflammatory benefits of acute exercise,17 however, a meta-analysis has shown that serum levels of IL-6 after an exercise bout do not differ between SCI and AB individuals.12 Indeed, Helge et al. (2011) in fact found greater IL-6 release from the upper limbs when compared with the lower limbs during whole-body exercise.19 More recently, Leicht et al. (2016) found that arm crank and cycling exercise, performed at the same relative, but not absolute exercise intensity, induce a similar inflammatory and anti-inflammatory response in AB individuals. The authors conclude that relative exercise intensity appears to be more important to the acute inflammatory response than modality, and therefore muscle mass (upper or lower limb exercise).18

To date, studies have not yet compared the effects of intensity-matched acute exercise at different intensities on pro and anti-inflammatory cytokines between AB and SCI individuals. This is important to determine effective exercise prescription to target anti-inflammatory action and for optimal health outcomes in SCI individuals. Therefore, the aim of the present study was to compare the effects of relative intensity-matched acute exercise at different intensities on the proinflammatory and anti-inflammatory cytokine balance between AB and SCI individuals. We hypothesized that the SCI group would have similar inflammatory responses post-exercise at the same relative intensity compared with the AB group at all intensities analyzed.

Material and methods

Study procedures were approved by the Universidade Federal de São Paulo Research Ethics Committee (0294/11) and were in agreement with Brazilian norms for research involving humans (Resolution 196; October 10, 1996). The Universal Trial Number (UTN) is U1111-1232-8142. All participants provided written informed consent to participate in the present study. This study refers to the same data set of a previous published study,20 although this current analysis is focused on the inflammatory response to an exercise bout.

Sample population

Thirty-one male volunteers (19 wheelchair-bound individuals with SCI and 12 AB controls) were screened for participation in this study. Participants with SCI were included in the study if they met the following criteria: (a) age above 18 years; (b) at least one year elapsed since the SCI; (c) paraplegic with complete traumatic SCI between the seventh thoracic vertebra and the first lumbar vertebra;21 (d) wheelchair as the only mean of locomotion; (e) normal stress electrocardiogram and (f) were physically active. Exclusion criteria included (a) diagnosed with cardiovascular disease, diabetes or acute inflammatory disease; (b) use of anti-inflammatory or dyslipidemia medication. The same inclusion and exclusion criteria were used for participants in the AB group (other than criteria regarding SCI).

Physically active SCI individuals were chosen due to the intensities used in the physical exercise sessions in the present study. For adults who are not already exercising, it is appropriate to start with smaller amounts of exercise and gradually increase intensity, frequency, and duration, as a progression towards meeting the guidelines.22 In this sense, aerobic exercise at high intensity would not be recommended for physically inactive individuals with SCI.

Volunteers from the AB group met the American College of Sports Medicne physical activity recommendations (at least 150 min of moderate-intensity physical activity per week) and were considered physically active.23 In the SCI group, volunteers should be weekly performing at least 90 min of moderate-intensity physical activity to be considered physically active.22

Of the 31 participants screened, four non-traumatic SCI individuals and four participants with incomplete SCI were initially excluded due to inclusion criteria. In addition, four participants (two SCI and two AB) did not return for a second or third session within a week after the first session. Finally, two AB volunteers were excluded from the analysis due to insufficient blood samples. In sum, nine complete SCI and eight AB individuals were included in this study (N = 17).

Volunteers from the AB group had ‘good’ cardiorespiratory fitness level [peak oxygen consumption (VO2peak) = 51.54 ml/kg/min] according to population norms,24 while in the SCI group (VO2peak = 34.5 ml/kg/min) participants could be described as ‘good’ to ‘excellent’ compared with other studies in SCI population.24–27

Height was measured with the volunteer lying down on a flat surface, and measurements were recorded at the distal points between the head and feet at a 90° position. Body mass of the SCI group was measured by an electronic scale that was adapted for use with wheelchairs (Tanita® 4521 wheelchair scale, IL, USA). The wheelchair was weighed first and then subtracted from the total weight of the volunteer and the wheelchair together, in order to determine the weight of the patient alone. Body mass of the AB group was measured on a digital scale (Seca Robusta 13, Hamburg, Germany).

Body composition was assessed via the air-displacement plethysmography method using the BOD POD® equipment (COSMED, Rome, Italy) and the analysis was performed as described with details by Lemos et al. (2016).28 The equipment was calibrated before each test, and all participants were asked to remove any excess clothing and to be measured while preferably wearing swimsuits. After that, volunteers entered the test chamber to measure body density. The BOD POD® calculates the volunteer’s body density and then uses the Siri’ formula (1961) to calculate their body fat percentage.29

Experimental design

The experimental design of this study was adapted from Tsao et al. 2012.30 Figure 1 shows the experimental design. Volunteers were assessed in the laboratory during five different sessions that were performed in the morning to avoid circadian variations in hormonal concentrations and physical performance. In the first session, participants were provided with comprehensive information about the study and were subjected to resting and stress electrocardiograms to verify cardiac limitations on performing high-intensity exercise. Volunteers were asked to return for a second session within a week after obtaining medical consent. Individuals who were not able to return within this timeframe were excluded.

Figure 1.

Figure 1

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Experimental desing of study. Volunteers were assessed in the laboratory during five different sessions. In the first session, participants were provided with comprehensive information about the study and were subjected to resting and stress electrocardiogram (ECG). In the second session, volunteers undertook an ergospirometry test to determine peak oxygen consumption (VO2peak) and ventilatory threshold 1 (VT1). In the following three sessions, all subjects completed three exercise sessions of different intensities that were conducted with an interval of at least 48 h and maximum seven days between sessions to ensure complete recovery from the previous session. The relative intensities of the exercise sessions were designed to achieve oxygen consumption (VO2) at VT1, 15% below VT1, and 15% above VT1 in both groups. The exercise volume of the first exercise session (third visit) was controlled so that participants in both groups exercised for 30 min. During the fourth visit, exercise intensity of the following two sessions was randomly determined by draw. During sessions at 15% below VT1 and 15% above VT1, exercise volume was calculated based on the subject’s energy expenditure at VT1 for 30 min.

In the second session, volunteers undertook an ergospirometry test to determine VO2peak and ventilatory threshold 1 (VT1). The VT1 refers to the point during exercise at which ventilation starts to increase at a faster rate than oxygen consumption (VO2) and reflects the exercise intensity corresponding to the beginning of blood lactate accumulation (increase in anaerobic metabolism).31 In the following three sessions, all subjects completed three exercise sessions at different intensities that were conducted with an interval of at least 48 h and maximum seven days between sessions to ensure complete recovery from the previous session. In all exercise days, volunteers arrived in a fasted state at the laboratory. The relative intensities of the exercise sessions were designed to achieve the speed that corresponds to VO2 at VT1, VO2 at 15% below VT1, and VO2 at 15% above VT1 in both groups. The intensities chosen in this study are based on the guidelines for physical exercise prescription for people with SCI which state that these individuals should perform exercise at moderate and vigorous intensity (moderate: VT1, vigorous: 15% above VT1) to attain the benefits of exercise.22 In addition, individuals who begin physical exercise programs should start with lower intensities (low: 15% below VT1).

The exercise volume of the first exercise session (third visit) was controlled so that participants in both groups exercised for 30 min at VT1. During the fourth visit, exercise intensity of the following two sessions was randomly determined (15% above VT1 and 15% below VT1).

During sessions at 15% below VT1 and 15% above VT1, exercise volume was calculated based on the subject’s calorie expenditure at VT1 for 30 min. Por exemplo, se um voluntário gastou 200 kilocalorie (Kcal) durante 30 minutos na sessão do VT1, na sessão seguinte o volume da sessão será correspondente ao momento em que o voluntário atingir o gasto calórico de 200 kcal. Energy expenditure in Kcal was measured by indirect calorimetry utilizing open circuit spirometry of the Cosmed K4 b2 metabolic analyzer (Rome, Italy).

Establishing VO2peak and ventilatory threshold (VT1)

During the second session, participants performed an incremental test until exhaustion in order to establish VO2peak and VT1. Volunteers of the AB group were tested on a conventional treadmill (Lifefitness® 9100HR, Schiller Park, IL, USA) whereas volunteers of the SCI group were tested on a treadmill with a running surface of 152 cm x 245 cm adapted for wheelchair use (Vacumed 13610 Large Research Treadmill, Ventura, CA, USA/ https://www.vacumed.com/zcom/product/Product.do?compid=27&prodid=688). Figure 2 shows both treadmills used in this study.

Figure 2.

Figure 2

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Treadmills used in the study. Volunteers of the AB group were tested on a conventional treadmill (panel A) whereas volunteers of the SCI group were tested on a treadmill adapted for wheelchair use (panel B).

The protocol to establish VO2peak was designed based on previous literature.26,32,33 Subjects in the AB group started the test on the treadmill at 1% incline and at a speed of 5 km/h for 3 min; speed was increased by 1 km/h per minute until maximum voluntary exhaustion. Volunteers in the SCI group initiated the test at 1% incline and at a speed of 6 km/h for 3 min; speed was increased by 1 km/h per minute until maximum voluntary exhaustion. Maximum voluntary exhaustion was determined based on the volunteer’s report of muscle fatigue, general fatigue, muscle or joint soreness, VO2 plateau (≤ 150 ml/min), attainment of the percentage of the age-predicted maximal heart rate (HRpeak) within ± 5 bpm, respiratory exchange ratio (RER) ≥ 1.10, or loss of coordination required to maintain the treadmill pace (running strides or wheelchair spinning).34 A gas analyzer was used to determine respiratory variables, such as VO2peak and VT1, as well as VT1 loads. VO2peak was estimated based on the highest relative VO2 (ml/Kg/min) obtained at the end of the test. In order to determine VT1, two independent evaluators observed the criteria adopted by Gaskill et al.35 These variables were obtained by analyzing pulmonary gas exchange using a gas analyzer (Quark PFT 4Ergo®, Cosmed, Rome, Italy). Heart rate (HR) was recorded in every 5 s using a short-distance telemetry system (RS800CX, Polar Electro Oy, Kempele, Finland).

Blood collection and analysis

Blood samples (20 ml each time) were collected 3 times from the median cubital vein at baseline, immediately after, and 30 min after the exercise sessions in tubes containing 100 µL of heparin sodium (125 IU). Blood was centrifuged at 690xg for 15 min at 4°C and plasma was stored in fractions at −80°C for further analysis.

Interleukin 1 receptor antagonist (IL-1ra) and Interleukin 1 beta (IL-1β) concentrations were assessed by commercial ELISA (R&D Systems®, Minneapolis, MN, USA). Interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10) and tumoral necrosis factor alpha (TNF-α) concentrations were assessed by MULTIPLEX assay (R&D Systems®, Minneapolis, MN, USA).

Statistical analysis

Results were compared through nonparametric analysis based on the sample size of this study (n = 17) and distribution of variables. Comparisons between groups were performed using the Mann–Whitney test. Friedman’s analysis of variance was used to compare differences based on data collection time within the same group (comparisons between baseline, immediately after and 30 min after exercise session). When significant differences were found using Friedman’s test, repeated Wilcoxon tests were performed to identify the time points for which the differences were observed. In this last test, the p value was corrected based on the number of comparisons performed (Bonferroni correction). For the comparisons between groups, the power and effect sizes calculations were conducted following the orientation of G*Power 3.1 manual (http://www.psychologie.hhu.de/fileadmin/redaktion/Fakultaeten/Mathematisch-Naturwissenschaftliche_Fakultaet/Psychologie/AAP/gpower/GPowerManual.pdf).

Analysis were performed using SPSS version 20.0 (SPSS Inc., Armonk, NY, USA) and G*Power version 3.1.9.4. The graphics were built in RStudio language using lattice36 and grid packages. Values are presented as individual values in dotplot graphics and medians, first and third quartiles, minimum and maximum values in boxplot graphics. Values in tables represent the median and first and third quartiles. The significance level adopted was P < 0.05, except when Bonferroni’s correction was performed. Also, a supplementary table of the cytokines values (Table 1 supplement) is available.

Results

Age, anthropometric and cardiorespiratory characteristics

Table 1 shows the results of age, anthropometric and cardiorespiratory characteristics of participants this study at baseline moment. Age (U = 31.5; P = 0.269; ω = 0.11; d = 0.41), height (U = 24.00; P = 0.086; ω = 0.23; d = 0.68), body fat percentage (U = 27.50; P = 0.265; ω = 0.53; d = 1.20), oxygen consumption (U = 35.50; P = 0.659; ω = 0.09; d = 0.30) and maximum heart rate (U = 25.50; P = 0.772; ω = 0.31; d = 0.80) showed no significant differences between the AB and SCI groups. Only the body mass was significant smaller in the SCI group than compared to the AB group (U = 13.00; P = 0.016; ω = 0.61; d = 1.30; Mann–Whitney test).

Table 1. Chronological age, anthropometric, cardiorespiratory and energy expenditure during three exercise sessions of subjects.

  AB (n = 8) SCI (n = 9) P value Power (1- β) Effect size (d)
Age (years) 27.0 (24.00–31.00) 29.00 (26.50–36.00) 0.247 0.11 0.41
Height (cm) 179.50 (172.33–183.50) 168.00 (164.50–175.50) 0.210 0.23 0.68
BM (kg) 75.70 (63.14–83.25) 60.66 (55.25–66.20)* 0.016 0.61 1.30
BF (%) 13.00 (11.88–15.50) 15.65 (11.68–21.75) 0.599 0.53 1.20
VO2base (ml/kg/min) 3.5 (2.8–4.2) 3.3 (3.3–3.6) 0.659 0.09 0.30
HRbase (bpm) 69 (64–70) 72 (66–76) 0.132 0.31 0.80
EE at 15% &lt; VT1(Kcal) 353.0 (325.25–402.5) 168.0 (127.5–220.0)* 0.001 0.99 3.16
EE at VT1 (Kcal) 355.0 (328.0–399.75) 172.0 (127.0–218.14)* 0.001 0.99 3.28
EE at 15% > VT1 (Kcal) 352.5 (329.25–401.75) 165.0 (125.5–216.0)* 0.001 0.99 3.25
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AB = able bodied; SCI = spinal cord injured; base = baseline; bpm = beats per minute; cm = centimeters; BM = body mass; kg = kilograms; BF = body fat; % = percentage; ml/kg/min = milliliter to kilograms to minutes; min = minute; VO2 = Oxygen Consumption; HR = Heart Rate; EE = Energy Expenditure; Kcal = Kilocalories; VT1 = Ventilatory Threshold 1; 15% < VT1 = Intensity at 15% below VT1; 15% > VT1 = Intensity at 15% above VT1.Values are expressed as median and first and third quartiles. * = different from the AB group.

Exercise protocol

When compared to the AB group, SCI volunteers have a smaller energy expenditure in the exercise intensity 15% below VT1 (U = 1.00; P = 0.001; ω = 0.99; d = 3.16), in VT1 (U = 0.00; P = 0.001; ω = 0.99; d = 3.28) and 15% above VT1 (U = 0.00; P = 0.001; ω = 0.99; d = 3.25, Mann–Whitney test) (Table 1). Friedman showed no significant differences in the energy expenditure in the AB group (X2 (2) = 2.00, P = 0.368) and in the SCI group (X2 (2) = 3.25, P = 0.197) between different exercise session (15% below VT1, VT1 and 15% above VT1).

Exercise volumes for the AB group during acute exercise sessions at 15% below VT1, VT1, and 15% above VT1 were 34.2 ± 0.9, 30 min, and 24.6 ± 0.9 min, respectively. In the SCI group, exercise volumes during acute exercise sessions at 15% below VT1, VT1, and 15% above VT1 were 34.7 ± 1.2, 30 min, and 24.2 ± 0.9 min, respectively.

Inflammatory mediators at baseline and during acute exercise at different intensities.

Interleukin – 6

During VT1 intensity session, the AB group had higher IL-6 concentrations immediately after the exercise session compared to baseline (T = −2.521; P = 0.012) (Figure 3B).

Figure 3.

Figure 3

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Interleukin 6 (IL-6; A, B and C) blood concentration (pg/mL) in able bodied (AB) (n = 8) and spinal cord injured (SCI) (n = 9) volunteers at baseline (Base), immediately after (after) and 30 min after exercise at 15% below ventilatory threshold 1 (VT1), in VT1 and 15% above VT1. a Significant difference from baseline for the same group. b Significant difference from the AB group.

Pro inflammatory cytokines

IL-1β concentration at baseline (U = 6.50; P = 0.005; ω = 0.83; d = 1.64) and 30 min after exercise (U = 5.00; P = 0.005; ω = 0.32; d = 0.82) at the intensity 15% below VT1 were higher for the SCI group compared with the AB group (Figure 4A). Baseline concentrations of IL-1β were higher in the SCI group compared to the AB group (U = 9.00; P = 0.009; ω = 0.47; d = 1.07) at VT1 intensity (Figure 4B).

Figure 4.

Figure 4

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Interleukin 1 beta (IL-1β; A, B and C), interleukin 2 (IL-2; D, E and F) and tumor necrosis fator alpha (TNF-α; G, H and I) blood concentration (pg/mL) in able bodied (AB) (n = 8) and spinal cord injured (SCI) (n = 9) volunteers at baseline (Base), immediately after (after) and 30 min after exercise at 15% below ventilatory threshold 1 (VT1), in VT1 and 15% above VT1. b Significant difference from the AB group.

The SCI group presented higher concentrations of IL-2 at baseline (U = 2.00; P = 0.002, ω = 0.87; d = 1.82), immediately after (U = 0.00; P = 0.008, ω = 0.73; d = 1.51) and 30 min after (U = 1.00; P = 0.006; ω = 0.43; d = 1.04) the exercise session at 15% below VT1 intensity compared with the AB group (Figure 4D). The SCI group presented the higher concentrations of IL-2 at baseline (U = 10.50; P = 0.024, ω = 0.63; d = 1.34), immediately after (U = 7.00; P = 0.009, ω = 0.57; d = 1.25) and 30 min after (U = 6.00; P < 0.006; ω = 0.43; d = 1.05) the exercise session at VT1 intensity compared with the AB group (Figure 4E). In addition, the SCI group had higher concentrations of IL-2 at baseline (U = 2.00; P = 0.002; ω = 0.65; d = 1.37), immediately after (U = 5.00; P = 0.005; ω = 0.26; d = 0.76) and 30 min after (U = 2.00; P < 0.002; ω = 0.36; d = 0.93) the 15% above VT1 intensity compared to the AB group (Figure 4F).

No significant difference in TNF-α concentrations were observed between groups at each collection time (P > 0.05) in any intensity of exercise (Figures 4G–I).

Anti-inflammatory cytokines

IL-1ra concentration was found to be significantly higher 30 min after the exercise session in the AB group compared with the SCI group (U = 12.00; P = 0.036; ω = 0.49; d = 1.13) at 15% below VT1 intensity (Figure 5A). In addition, IL-1ra was higher immediately after VT1 exercise session in the AB group compared with the SCI group (U = 8.00; P = 0.007; ω = 0.79; d = 1.57) (Figure 5B). Finally, IL-1ra was found to be higher after the exercise session at 15% above VT1 intensity in the AB group compared to the SCI group (U = 10.00; P = 0.037; ω = 0.27; d = 0.82) (Figure 5C).

Figure 5.

Figure 5

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Interleukin 1 receptor antagonist (IL-1ra; A, B and C), interleukin 4 (IL-4; D, E and F) and interleukin 10 (IL-10; G, H and I) blood concentration (pg/mL) in able bodied (AB) (n = 8) and spinal cord injured (n = 9) (SCI) volunteers at baseline (Base), immediately after (after) and 30 min after exercise at 15% below ventilatory threshold 1 (VT1), in VT1 and 15% above VT1. b Significant difference from the AB group.

IL-4 (Figures 5D–F) and IL-10 (Figures 5G–I) concentrations at baseline, immediately after and 30 min after all exercise sessions were lower in the SCI group (IL-4 and IL-10 concentrations were undetected at all collection times) compared with the AB group (P <0.001; ω = 0.17-0.99; d = 0.56-2.95, for all collection times).

Discussion

In the present study, the main objective was to compare the effects of relative intensity-matched acute exercise at different intensities on the proinflammatory and anti-inflammatory cytokine balance between AB and SCI individuals. Contrary to our hypothesis, SCI individuals had a consistently attenuated acute systemic anti-inflammatory cytokine response when compared to AB individuals at the same relative exercise intensity. This result is evident both in the increase of IL-6 only found in the AB group immediately after the physical exercise at VT1 intensity (≈ 55% of VO2 peak) and also by the difference in IL-1ra concentrations between the groups after the exercise session in all intensities assessed. In this context, we suggest that SCI individuals with good physical fitness may have to perform physical exercise at a higher volume or energy expenditure to obtain benefits similar to AB individuals.

Cytokines can serve as markers of inflammation, and some have been associated with pro-inflammatory effects, whereas others with anti-inflammatory effects. In the present study, we found higher concentrations of the pro-inflammatory cytokine IL-2 as well as lower concentrations of the anti-inflammatory cytokines IL-10 and IL-4 in the SCI group compared to the AB group, at the same collection times in all conditions. However, we found no difference in IL-6 and TNF-α baseline concentrations between groups, cytokines which are usually high in individuals with SCI.5,12 We suggest that the good cardiorespiratory fitness and the absence of metabolic disorders20 may have attenuated some of the typical increase of proinflammatory cytokines found in SCI populations.

Even without differences in IL-6 and TNF-α, the higher concentrations of baseline IL-2, and lower IL-10 and IL-4 concentrations found in this study likely indicate a state of chronic systemic inflammation in these SCI individuals. IL-2 (a T helper 1 derived cytokine) has been shown to promote chronic inflammation, being associated with a variety of disease states, playing a critical role in regulating mainly cellular and humoral chronic inflammatory responses.37 IL-10 and IL-4 are two important anti-inflammatory cytokines, that have been shown to be reduced in individuals with chronic inflammation compared to healthy controls.38,39 Considering that chronic SCI may lead to systemic inflammation due to visceral adiposity, for example,5,40 our data corroborates the current literature.

IL-6 is a cytokine that is known to have both pro and anti-inflammatory effects.16,17 Chronic increases of IL-6 in the circulation is related with systemic inflammation and cardiovascular disease while acute increases of IL-6, as seen after physical exercise, stimulate an anti-inflammatory cascade.13,16,17 In the present study, we found higher concentrations of IL-6 immediately after the exercise session at VT1 intensity in AB participants, but not in SCI participants. It is critical to highlight, however, that the literature is controversial when it comes to the variations of IL-6 during exercise performed by the upper and lower limbs.19,41 Steensberg et. al (2002) for example, reported no changes in IL-6 release during the first hour of leg exercise.41 On the other hand, Helge et al. (2011) reported a greater release of IL-6 from the arms when compared to the legs during exercise performed by the whole body.19 Given this, it is possible that other parameters besides the volume of active muscle mass, such as the physical fitness and body composition, could influence the amount of IL-6 released by the muscle.

Besides the amount of muscle mass engaged during the exercise session, the high level of physical fitness of the SCI individuals of our study might also have led to an attenuation of IL-6 response to exercise, since previous studies have already demonstrated the impact of physical conditioning on cytokine production by the skeletal muscle.42 For instance, the acute plasma IL-6 response after exercise has been shown to be lower in trained individuals.17 Accordingly, it has been speculated that differences in training status would affect the muscle glycogen content,17,42 and thence IL-6 release. These factors may explain why SCI individuals showed a smaller amount of IL-6 released from the upper limbs compared with the lower limbs of the AB group at the same relative workload.

Interestingly, a study that aimed to evaluate the inflammatory response of 20 healthy men who exercised with arm cycle ergometer for 45 min at 60% of VO2peak and cycle leg ergometer for 45 min at 60% of VO2peak found significant increases in IL-6 for both groups after the exercise session compared to baseline, but no difference between conditions was found.18 It is important to note that VO2peak was evaluated in each specific ergometer, that is, the volunteers performed the exercise bout at the same relative intensity as evaluated in the present study.

Corroborating the previous literature, this study did not observe any increase of anti-inflammatory cytokines IL-10 and IL-1ra, after the exercise sessions at any intensity, when we compared the different collection times between both groups. With this in mind, our results may stem from the short period of post-exercise sampling used. Additional samples 1–2 h after exercise may have been useful to identify any delayed anti-inflammatory response. However, a significant difference in IL-1ra between groups was found immediately after the exercise session at VT1 and 15% above VT1, possibly due to a small increase of this cytokine after exercise in the AB group.

The limitations of the present study should be acknowledged. The small number of volunteers, although not uncommon in studies with SCI population, increases the likelihood of type II error (low statistical power). The presence of a SCI group with low fitness level would help to distinguish if the results found in this study are related to fitness level and/or active muscle mass. Also, the post-exercise proinflammatory and anti-inflammatory cytokine balance during a longer recovery period was not followed. Finally, another limitation was the order of the exercise intensities (VT1 on the first day of trial, followed by 15% below VT1 and 15% above VT1 in a random fashion). Although the reason for this arrangement was to compare cytokine levels after establishing similar energy expenditures from exercises with different intensities and durations, this arrangement possibly posed a threat to the study’s internal validity.27,43 In future trials, different exercise intensities should be randomly performed to avoid such a bias.

Conclusion

The present results do not support our hypothesis that the SCI group would have similar inflammatory responses post-exercise at the same relative intensity compared with the AB group in all intensities analyzed. The SCI group had an attenuated inflammatory response when compared to AB individuals after exercise at VT1 intensity. Therefore, individuals with SCI may have to perform physical exercise at a higher volume or energy expenditure than AB individuals to obtain similar anti-inflammatory benefits of acute exercise. The findings of this study may only be extended to SCI individuals with good physical fitness and without metabolic disorders.

Supplementary Material

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Acknowledgements

We thank the “Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq)” and “Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)”.

Disclaimer statements

Contributors None.

Funding None.

Conflicts of interest Authors have no conflict of interests to declare.

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