Multiple sclerosis (MS) is defined as an immune-mediated inflammatory, neurodegenerative, and demyelinating disease that impacts the central nervous system (CNS) in young individuals. Although there are controversies regarding the exact mechanism of disease initiation, it is well known that inflammation plays an important role in pathogenesis of the disease. As important players in inflammation, cytokines, and adipokines, the effects of post-exercise on these factors in MS patients are still in the early stages of research, and results are in doubt. Due to the above differences, this study was undertaken to comprehensively evaluate randomized clinical trials (RCTs) examining the effects of exercise on inflammatory markers that have shown moderate to large changes in PwMS.
A search was independently conducted through electronic databases including Scopus, Web of Science, The Cochrane Library, and PubMed by two researchers to find studies addressing the effects of physical activity and/or exercise training on serum levels of inflammatory markers in PwMS. The search language was restricted to English and Persian. The search date was limited to studies that were published from January 2003 to April 2022. This systematic review was conducted using specific keywords such as “multiple sclerosis” AND (“exercise” OR “yoga” OR “physical endurance” OR “exercise movement techniques” OR “resistance training”) AND (“interleukins” OR “tumor necrosis factor-alpha” OR “cytokines” OR “inflammation” OR “interferons” OR “adipokines” OR “leptin” OR “chemokines”). The two reviewers conducted the searches independently and prescreened the initial stage of the study selection, including the analysis of titles and abstracts. In the second stage, the full-text studies were evaluated to select them according to the eligibility criteria. A third author was responsible for supervising the procedure and resolving any discrepancies.
All RCTs that evaluated the effect of any exercise or physical activity on the serum level of inflammatory markers in MS patients were included. Cytokines, chemokines, and adipokines were among the inflammatory markers evaluated in the blood and CSF in this research. Studies included had to satisfy the following criteria: (1) RCTs if they were well described and of high quality, with defined outcomes; (2) studies on MS patients who engage in regular physical activity; (3) research on proinflammatory and anti-inflammatory cytokines or adipokines. Moreover, studies with the following criteria were excluded from the current review: articles not in English or Persian, nonhuman trials, interventions besides supplements and medicines, absence of full-text studies, duplicate reports, reviews, studies, comments, opinion pieces, methodological reports, and conference abstracts. Figure 1 depicts the screening process.
Data from the studies were independently collected and recorded in a Microsoft Excel database by two reviewers. Again, these processes were supervised by a third researcher. Variables extracted included the first author’s name, gender, sample size, age, disease status, Expanded Disability Status Scale (EDSS), type of exercise, duration and frequency of exercise, evaluated cytokines, a secondary outcome, type of sampling, and final results of each paper.
In total, 7529 papers were found; 3490 duplicates and 4039 articles that did not fulfill the inclusion criteria were removed, leaving 1046 papers for abstract and title screening. Following a full-text review, 22 articles were chosen for further analysis. The PRISMA flowchart shows a summary of the search and research selection process (Figure 1).
Figure1:PRISMA flow diagram study selection and inclusion process
Interleukin-6 was the most commonly assessed inflammatory marker, which was reported in 14 out of 22 studies[20][22][23][25][26][27][28][29][30][31][32][33][34][35]. The majority of the research showed no considerable changes in IL-6 levels, including five studies after using ergometers [22][26][27][28][30], two studies with combined training [25][34], one study after aerobic training [23], and another study with resistance exercise [29]. Three studies reported a decrease after 8 and 12 weeks (t.i.w.) of combined training [31][33] and 12 weeks of resistance exercise (b.i.w.) [32]. Only two studies evaluated high levels of IL-6 after one session of fitness [20] and 8 weeks (b.i.w.) of cycle ergometer exercises[35].
TNF-α was studied in 11 of 22 trials [16][22][23][25][26][28][29][34][36][37][38], with the majority of studies showing no significant difference in TNF-α levels with varying exercises from one session for 24 weeks [23][26][29][34][36][37]; 8 weeks of aerobic (t.i.w.) exercise [16], 12 weeks (t.i.w.) of combined training [25], and one session of ergometer training [22] resulted in lower serum TNF-α levels. Only one study reported an increase in serum TNF-α level following 8 weeks (t.i.w.) of cycle ergometer exercises [28].
Eight studies reported IFN-γ serum levels; however, three studies reported no significant changes after three treadmill sessions [23], 12 weeks (t.i.w.) of combined exercise [25], and 24 weeks (b.i.w.) of resistance exercises [38]. Moreover, three studies evaluated a lower level of IFN-γ after 8 weeks of combined training [37][38][39] and 8 weeks of resistance exercises [29]. In contrast, in two other studies, IFN-γ was increased after 8 weeks of ergometer exercises [28] and 12 weeks of combined exercise [31].
0Two studies reported a decrease in post-exercise serum levels (8 to 12 weeks, 2 to 3 days a week) following resistance and aqua training, respectively [32][40]. Only one study reported no significant changes after combined training [34], while another reported no significant changes after 8 weeks of ergometer exercises in serum levels of IL-12p70 [35].
Eleven trials assessed IL-10 levels, and no noticeable changes in IL-10 levels were detected after performing combined exercises in three studies [25][34][37], and after resistance [36], Pilates [47], and aerobic exercises [16] in one study each. Although four studies reported a significant reduction in IL-10 level after resistance training [35], ergometer exercises [22][35], and three sessions of aerobic exercises [23], one research showed an enhanced IL-10 level after 8 weeks (t.i.w.) of combination training [33].
Two trials found no significant differences after 8 weeks (t.i.w.) of combined training [41], three treadmill sessions [23], and 24 weeks of resistance exercise [36]; White et al. and Kierkegaard et al. found a decline in serum IL-4 levels after 8 and 12 weeks (b.i.w.) resistance training, respectively.
Three trials examined leptin following exercise, and two of them also assessed adiponectin. Two of them reported a decline in leptin serum levels after one session on an ergometer [22] and 8 weeks of aerobic training [16]. Only Ebrahimi et al. reported no considerable difference after 10 weeks (t.i.w.) of WBV. Furthermore, two studies following aerobic training [16] and one session of ergometer training [22] observed an increase and no changes in adiponectin serum levels, respectively.
Three studies from five trials [20][26][27][30][47] reported a boost in BDNF serum levels after 3 and 9 (b & t.i.w.) weeks of cycle ergometry [26][27], and 8 weeks of Pilates training [47]. BDNF serum levels remained unchanged in two studies with ergometer exercises and fitness interventions [20][30].
Functional muscle strength [18][29][30][32][36][39] and fatigue [16][18][26][29][30][32] were the most examined factors, as evidenced by six articles, the majority of which showed better muscle function, and half of which reported fatigue treatments. Five trials reported an improvement in QoL and walking function after the period of intervention [18][22][30][31][32][35][36]. .
Table 2. Sample characteristics and main findings of the reviewed studies.
First Author |
Gender |
Sample Size |
Mean Age |
Disease Status |
Mean EDSS |
Type of Exercise |
Duration and Frequency of Exercise |
Evaluated Cytokines |
Main Findings |
Tadayon Zadeh F |
Female |
MST:15 MSC:15 |
Range (25–40) |
- |
≤6 |
Endurance, resistance, balance |
8 wks (t.i.w.), 40–70% HR max |
IL-6, CRP, IL-10 |
↓: IL-6, CRP ↑: IL-10 |
Devasahayam. A |
Both |
MST:14 MSC:8 |
54.07 (8.46) |
SPMS PPMS |
6–6.5 |
Fitness |
One session |
BDNF IL-6 |
↔: BDNF ↑: IL-6 |
Faramarzi M. |
Female |
MST:46 MSC:43 |
Range (18–50) |
RRMS |
Not reported range (0–8) |
Combined stretching, balance, pilates, resistance, endurance |
12 wks (t.i.w.) |
IL-6, IFN-γ, CRP |
↓:IL-6, CRP ↑: IFN-γ |
Rezaee S. |
Both |
MST:10 MSC:10 |
28.9 ± 3.3 |
RRMS |
2.2 ± 0.4 |
Aerobic training |
6 wks (t.i.w.) 60% VO2 max |
TNF- α |
↓: TNF- α |
Nejatpour S |
Male |
MST:13 MSC:12 |
- |
- |
Range (2.5 –5) |
Aqua training |
8 wks (t.i.w.) 75% VO2 max |
IL-12, Il-17 |
↓:IL-12, IL-17 |
Barry A |
Both |
MST:9 HC:10 |
35.33 ± 2.12 |
RRMS |
2.17 ± 0.40 |
Cycle ergometer |
8 wks (b.i.w.), 65–75% VO2 max |
IL-10, IL-12p70, IL-6 |
↑: IL-6, 12 p70 ↓: IL-10 |
Berkowitz, S. |
Female |
MST:15 MSC:10 |
33.8 ± 7.8 |
- |
1.5 |
Aerobic (treadmill) 50–80 VO2 max |
3 sessions |
IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF-α |
↓: IL-10 ↔: IL-4, IL-17A, IFN-γ, TNF-α, IL-6 |
Eftekhari E. |
Female |
MST:15 MSC:15 |
34.46 ± 7.29 |
RRMS |
Range (2–6) |
Pilates training |
8 wks (t.i.w.) |
IL-10, BDNF |
↔: IL-10 ↑: BDNF |
Majidnasab N. |
Female |
MST:30 HC:15 MSC:5 |
28.23 ± 3.65 |
RRMS |
2.11 ± 0.76 |
Arm, cycle ergometer |
One session 60–70% VO2 max |
IL-6, IL-10, TNF- α, leptin, adiponectin |
↔: IL-6, adiponectin ↓: TNF- α, IL-10, leptin |
Mokhtarzade M. |
Female |
MST:22 MSC:8 |
32.04 ± 2.81 |
RRMS |
1.84 ± 0.35 |
Aerobic |
8 wks (t.i.w.) 60% max watt |
IL-10 TNF- α Leptin adiponectin |
↔: IL-10 ↓: leptin, TNF- α ↑: adiponectin |
Alvarenga-Filho H |
Both |
MST:8 MSC:10 HC:10 |
41.1 ± 12.9 |
RRMS |
0–2.5 |
Resistance training, cycle ergometer, pilates |
12 wks (t.i.w.) |
IL-6, IL-10, IL-21, IL-22, IL-17, TNF-α, IFN-γ |
↓:IL-22 ↔: IL-17, -10, -21, TNF- α, IL-6, IFN-γ |
Briken S. |
Both |
MST:28 MSC:9 |
49.9 ± 7.6 |
PPMS, SPMS |
4.9 ± 0.9 |
Endurance, arm ergometer, cycle ergometer, rowing |
9 wks (b & t.i.w.) |
BDNF, IL-6 |
↔: IL-6 ↑: BDNF |
Kierkegaard M. |
Both |
MST:20 |
36.3 ± 7.6 |
RRMS |
1.5 |
Resistance training |
12 wks (b.i.w.) 80% 1 RM |
IL-1ra, -4, -5, -6, -7, -8, -12p70, -13, -17 |
↓: all in blood ↔: all in CSF |
Deckx N. |
Both |
MST:29 MSC:16 |
47 ± 2 |
RRMS and CPMS |
3 ± 0.2 |
Endurance, resistance |
12 wks (t.i.w.) |
IL-6, IL-10, IL-12p70, TNF- α |
↔: all |
Ebrahimi.A |
Both |
MST:16 MSC:14 |
38.76 ± 9.66 |
RRMS |
3.11 ± 0.99 |
WBV |
10 wks (t.iw.) |
leptin |
↔: leptin |
Kjølhede T. |
Both |
MST:16 MSC:16 |
44.6 ± 7 |
RRMS |
2.9 ± 1 |
Progressive resistance training |
24 wks (b.i.w.) |
IL-1β, IL-4, IL-10, IL-17F, IL-23, TNF-α, IFN-γ |
↔: all |
Bansi J. |
Both |
WT:24 LT:28 |
44.6–56.3 |
- |
4.65 |
Cycle ergometer, aquatic bike |
3 wks, 70% H-peak |
BDNF, TNF- α, IL-6, sIL-6r |
↑: BDNF ↔: NGF, TNF-α, IL-6, sIL-6r |
Golzari Z. |
Female |
MST:10 MSC:10 |
32.15 ± 7.57 |
- |
2.14 ± 1.06 |
Stretch, aerobic, resistance, endurance |
8 wks (t.i.w.) |
IFN-γ, IL-4, IL-17 |
↓: IFN-γ, IL-17 ↔: IL-4 |
Castellano V. |
Both |
MST:11 MSC:11 |
40 ± 10 |
- |
0–5.5 |
Cycle ergometer |
8 wks (t.i.w.) 60% VO2 max |
TNF- α, IL-6, IFN-γ |
↔: IL-6 ↑: TNF- α, IFN-γ |
White L.J. |
Female |
MST:11 |
47 ± 12 |
- |
3.8 ± 0.9 |
Resistance training |
8 wks (b.i.w.) 50–70% MVC |
IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, CRP |
↓:IL-4, IL-10, IFN-γ, IL-2, CRP ↔: IL-6, TNF- α |
Schulz K. |
Both |
MST:15 MSC:13 |
42 ± 9.5 |
RRMS, SPMS |
2.5 ± 1.4 |
Cycle ergometer |
8 wks (b.i.w.) 75% VO2 max |
BDNF, NGF, IL-6, sIL-6r |
↔: All |
Heesen C. |
Both |
MST:15 MSC:13 HC:20 |
39.8 |
RRMS, SPMS, PPMS |
2.3 ± 0.2 |
Cycle ergometer (resistance + endurance) |
8 wks (b.i.w.) 60% VO2 max |
IFN-γ, TNF- α, IL-10 |
↓: IFN-γ ↔: TNF- α, IL-10 |
Weeks = wks; three times a week= (t.i.w.); two times a week = (b.i.w.); two and three times a week= (b & t.i.w.), not reported = (-), MS = multiple sclerosis; IL = interleukin; TNF-α = tumor necrosis factor-alpha; RCT = randomized controlled trial; RRMS = relapsing-remitting multiple sclerosis; PPMS = primary progressive multiple sclerosis; CNS: central nervous system ; SPMS = secondary progressive multiple sclerosis; CPMS = chronic progressive multiple sclerosis; BDNF = brain-derived neurotrophic factor ; NGF = nerve growth factor; CRP = C-reactive protein; IFN-ɣ = interferon-γ; EDSS = Expanded Disability Status Scale; IL-1Ra = IL-1 receptor antagonist; Th = T-helper; ↓:increased; ↑:decreased; ↔: no significant changes; MST: MS training group; MSC: MS control group; HC: healthy control group; WT: water training group; LT: land training group.
The current review did not provide a consensus on the effects of different exercise training protocols on the serum level of inflammatory markers in patients with MS. This may be attributed to variations in the population gender, design and duration of studies, and inflammatory marker measurement protocols. Although it was indicated that acute exercise induces short-term inflammation followed by a mid-term anti-inflammatory environment, there are still many unanswered questions about the beneficial methodological flaws in the face of inflammatory factors.