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More gain, less pain: How resistance training affects immune system functioning in multiple sclerosis patients: A review

  • Nada Sherif Amin
    Affiliations
    Department of Pharmacology and Toxicology, Molecular Pharmacology Research Group, Faculty of Pharmacy and Biotechnology, Head of Molecular Genetics and Pharmacology Research Group, German University in Cairo, Cairo 11835, Egypt
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  • Hend M. El Tayebi
    Correspondence
    Corresponding author.
    Affiliations
    Department of Pharmacology and Toxicology, Molecular Pharmacology Research Group, Faculty of Pharmacy and Biotechnology, Head of Molecular Genetics and Pharmacology Research Group, German University in Cairo, Cairo 11835, Egypt
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Published:November 11, 2022DOI:https://doi.org/10.1016/j.msard.2022.104401

      Highlights

      • Resistance training improves many aspects in the physical and emotional wellbeing of multiple sclerosis patients.
      • In resistance trained individuals, multiple immune components are differentially expressed.
      • Resistance training may be beneficial for multiple sclerosis patients via altering their immune system profiles.
      • The alteration in the immune system profiles of multiple sclerosis patients may be the underlying molecular mechanism by which resistance training contributes to the overall wellbeing of these individuals.
      • Resistance training may be an exceedingly useful exercise modality to be incorporated for multiple sclerosis patients as a non-pharmacological disease-modifying therapy.

      Abstract

      Multiple sclerosis (MS) is characterized by a complex etiology that is mirrored by the perplexing and inconsistent treatment responses observed across different patients. Although epigenetic research has garnered rightful interest in its efforts towards demystifying and understanding aberrant responses to treatment, the interim undoubtedly requires alternative non-pharmacological approaches towards attaining more effective management strategies. Of particular interest in this review is resistance training (RT) as a non-pharmacological exercise-based interventional strategy and its potential role as a disease-modifying tool. RT has been reported across literature to positively influence numerous aspects in the quality of life (QoL) and functional capacity of MS patients, and one of the attributes of these benefits may be a shift in the immune system of these individuals. RT has also been proven to affect different immune system key players associated with MS pathology. Ultimately, this brief review aims to provide a potential yet crucial link between RT, alterations in the expression profile of the immune system, and finally an imminent improvement in the overall well-being and QoL of MS patients, suggesting that utilizing RT as an interventional exercise modality may be an effective strategy that would aid in managing such a complex and debilitating disease.

      Keywords

      1. Introduction

      Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) that affects more than 2.5 million people globally (
      • Dilokthornsakul P.
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      • Allen R.R.
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      Multiple sclerosis prevalence in the United States commercially insured population.
      ). It primarily results from an immune-mediated attack of self-reactive lymphocytes on components of the myelin sheath. Initiation of the disease often occurs in the presence of a genetic predisposition (
      • Sawcer S.
      • Franklin R.J.M.
      • Ban M.
      Multiple sclerosis genetics.
      ;
      • Patsopoulos N.A.
      Genetics of multiple sclerosis: an overview and new directions.
      ), but other risk factors include smoking, obesity (
      • Guerrero-García J.
      • Carrera-Quintanar L.
      • López-Roa R.I.
      • Márquez-Aguirre A.L.
      • Rojas-Mayorquín A.E.
      • Ortuño-Sahagún D.
      Multiple sclerosis and obesity: possible roles of adipokines.
      ), vitamin D deficiency (
      • Sintzel M.B.
      • Rametta M.
      • Reder A.T.
      Vitamin D and multiple sclerosis: a comprehensive review.
      ), as well as exposure to Epstein-Barr Virus (EBV) (
      • Hedström A.
      • Bäärnhielm M.
      • Olsson T.
      • Alfredsson L.
      Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis.
      ,
      • Hedstrom A.K.
      • Baarnhielm M.
      • Olsson T.
      • Alfredsson L.
      Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis.
      ,
      • Hedström A.
      • Alfredsson L.
      • Lundkvist Ryner M.
      • Fogdell-Hahn A.
      • Hillert J.
      • Olsson T
      Smokers run increased risk of developing anti-natalizumab antibodies.
      ,
      • Hedström A.K.
      • Ryner M.
      • Fink K.
      • Fogdell-Hahn A.
      • Alfredsson L.
      • Olsson T.
      • et al.
      Smoking and risk of treatment-induced neutralizing antibodies to interferon β-1a.
      ;
      • Handel A.E.
      • Williamson A.J.
      • Disanto G.
      • Dobson R.
      • Giovannoni G.
      • Ramagopalan S.V
      Smoking and multiple sclerosis: an updated meta-analysis.
      ;
      • Hawkes C.H.
      Smoking is a risk factor for multiple sclerosis: a metanalysis.
      ;
      • Alfredsson L.
      • Olsson T.
      Lifestyle and environmental factors in multiple sclerosis.
      ;
      • Nielsen T.R.
      • Rostgaard K.
      • Nielsen N.M.
      • Koch-Henriksen N.
      • Haahr S.
      • Sørensen P.S.
      • et al.
      Multiple sclerosis after infectious mononucleosis.
      ). The management of MS relies on three strategies: acute relapse management, symptomatic management, as well as the use of immune-modulating, disease-modifying pharmacological therapies (DMT) (
      • Doshi A.
      • Chataway J.
      Multiple sclerosis, a treatable disease.
      ).
      The insurmountable barrier of inconsistent treatment responses, along with the complexity of the disease and its ensuing symptoms, have led to the exploration of non-pharmacological interventional approaches for the improvement of patients’ welfare (
      • Salomè A.
      • Sasso D'Elia T.
      • Franchini G.
      • Santilli V.
      • Paolucci T
      Occupational therapy in fatigue management in multiple sclerosis: an umbrella review.
      ;
      • De-Bernardi-Ojuel L.
      • Torres-Collado L.
      • García-de-la-Hera M.
      Occupational therapy interventions in adults with multiple sclerosis or amyotrophic lateral sclerosis: a scoping review.
      ). These include approaches such as patient education (
      • Wendebourg M.J.
      • Heesen C.
      • Finlayson M.
      • Meyer B.
      • Pöttgen J.
      • Köpke S.
      Patient education for people with multiple sclerosis-associated fatigue: a systematic review.
      ), dietary modifications (
      • Riccio P.
      • Rossano R.
      Nutrition facts in multiple sclerosis.
      ;
      • Bagur M.J.
      • Murcia M.A.
      • Jiménez-Monreal A.M.
      • Tur J.A.
      • Bibiloni M.M.
      • Alonso G.L.
      • et al.
      Influence of diet in multiple sclerosis: a systematic review.
      ), physiotherapy and rehabilitation (
      • Paltamaa J.
      • Sjögren T.
      • Peurala S.
      • Heinonen A.
      Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.
      ), as well as physical exercise (
      • Halabchi F.
      • Alizadeh Z.
      • Sahraian M.A.
      • Abolhasani M.
      Exercise prescription for patients with multiple sclerosis; potential benefits and practical recommendations.
      ). A recent meta-analysis has implied the promising role of several patient education programs in teaching patients how to effectively manage fatigue, one of the most commonly reported and inconvenient symptoms of MS (
      • Asano M.
      • Finlayson M.L.
      Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication.
      ). Numerous studies have also made the association of a high-fat diet and a high body mass index (BMI) before the age of 20 with an exacerbation in inflammation and an increased risk for MS, respectively (
      • Riccio P.
      • Rossano R.
      Nutrition facts in multiple sclerosis.
      ;
      • Hadgkiss E.J.
      • Jelinek G.A.
      • Weiland T.J.
      • Pereira N.G.
      • Marck C.H.
      • van der Meer D.M.
      The association of diet with quality of life, disability, and relapse rate in an international sample of people with multiple sclerosis.
      ). Physiotherapy has been shown to have significant benefits for MS patients harbouring mild to moderate levels of disability (
      • Paltamaa J.
      • Sjögren T.
      • Peurala S.
      • Heinonen A.
      Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.
      ).
      Many symptoms of MS, including fatigue, pain, as well as ataxia, imminently result in reduced physical activity of the patient, with subsequent deconditioning. It has been shown that physical exercise is able to reduce physical impairments associated with deconditioning (
      • Sandoval A.E.G.
      Exercise in multiple sclerosis.
      ). Appropriate physical exercise is recently being recommended by multiple healthcare specialists and is believed to affect several fitness-related aspects in MS patients, including cardiovascular fitness, muscle strength, flexibility, respiratory function, cognition, among others (
      • Motl R.W.
      • Sandroff B.M.
      Benefits of exercise training in multiple sclerosis.
      ;
      • Dalgas U.
      • Stenager E.
      • Ingemann-Hansen T.
      Review: multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training.
      ). Of particular interest in this review is an exercise modality called resistance training (RT), its molecular impact on the immunity of MS patients, and the ensuing physical and mental changes that take place. First, published literature demonstrating the favorable outcomes of RT in MS patients will be reviewed. Then, effects of RT on various immune system key players that have been previously reported will be summarized. In order to begin establishing a potential immunomodulatory role of RT in MS patients, inflammatory key players in the aforementioned segment will be briefly reviewed in light of their most important roles in MS pathology. Finally, to pin this garnered notion that RT may indeed be exceedingly beneficial for MS patients, published literature investigating the impact of RT on the immunity of MS patients observed through clinical trials will be reviewed. Ultimately, we aim to establish a potential critical role for RT as a non-pharmacological exercise-based interventional approach in MS.

      1.2 Methodology

      For the purpose of this review, literature search was conducted on PubMed and Scopus databases using the following terms in different combinations according to the review sub-section: resistance training, immune function, multiple sclerosis. The following filters were also applied: publications that are a maximum of 10 years old, are in English language and are open access, and finally that address the specific questions based on the corresponding sub-sections of the review, as mentioned in the following flowchart.
      *Relevancy was based on literature demonstrating the physical/mental changes ensuing in MS patients following RT and a maximum of 1 additional exercise modality.
      **Relevancy was based on literature demonstrating how RT influences immune system components in trained individuals.
      ***Relevancy was based on trials investigating how resistance training influences different components of the immune system in multiple sclerosis patients.

      2. Resistance training in MS

      RT or strength training has recently garnered interest as a non-pharmacological exercise-based interventional approach in several neurodegenerative disorders, including MS. RT is regarded as the main universal exercise approach for increasing muscle mass in humans (
      • Schoenfeld B.J.
      • Contreras B.
      • Krieger J.
      • Grgic J.
      • Delcastillo K.
      • Belliard R.
      • et al.
      Resistance training volume enhances muscle hypertrophy but not strength in trained men.
      ), mediated through both neural factors (
      • Carroll T.J.
      • Selvanayagam V.S.
      • Riek S.
      • Semmler J.G.
      Neural adaptations to strength training: moving beyond transcranial magnetic stimulation and reflex studies.
      ), having been validated through electromyography studies, recordings from single motor units, among other studies (
      • Sale D.G
      Neural adaptation to resistance training.
      ), as well as changes in the morphology of the muscles (muscle hypertrophy), through several mechanisms, including the phosphorylation of P70S6 kinase and myofibrillar protein synthesis (
      • Terzis G.
      • Spengos K.
      • Mascher H.
      • Georgiadis G.
      • Manta P.
      • Blomstrand E.
      The degree of p70S6k and S6 phosphorylation in human skeletal muscle in response to resistance exercise depends on the training volume.
      ;
      • Burd N.A.
      • Holwerda A.M.
      • Selby K.C.
      • West D.W.D.
      • Staples A.W.
      • Cain N.E.
      • et al.
      Resistance exercise volume affects myofibrillar protein synthesis and anabolic signalling molecule phosphorylation in young men.
      ). In this section, reported published evidence regarding the favorable physical and/or mental effects of RT in MS patients will be reviewed.
      Two meta-analyzes compared the effects of RT on MS patients. In the first one, the studies included patients with EDSS ranging from 1.5 to 7, the duration of the interventions ranged from 8 to 24 weeks, and RT was applied in the form of percentages of one-repetition maximum of a certain movement, percentages of body weight, or absolute weights. Findings of this meta-analysis showed that RT significantly improved muscle strength (p = 0.013), short-walk performance (p = 0.006), long-walk performance (p < 0.05), and several functional mobility measures including 2 min walk test (2MWT), sitting-to-standing (5STS), stair climb, 3 min step test, and time-up-and-go, all with p-values < 0.05. Additionally, improvements in fatigue were also reported (p < 0.001) irrespective of the intervention duration (
      • Taul-Madsen L.
      • Connolly L.
      • Dennett R.
      • Freeman J.
      • Dalgas U.
      • Hvid L.G.
      Is aerobic or resistance training the most effective exercise modality for improving lower extremity physical function and perceived fatigue in people with multiple sclerosis? a systematic review and meta-analysis.
      ). The second meta-analysis included 7 MS trials ranging from 3 to 6 months and including patients with EDSS between 1 and 6.5 concluded significant improvements in muscle strength (p = 0.005), fatigue, functional capacity, QoL, and muscle power, all with p-values < 0.05 across the different studies. The types of RT protocols included in these studies ranged from lower body/machine exercises, weighted vest use, or home-based RT (
      • Cruickshank T.M.
      • Reyes A.R.
      • Ziman M.R.
      A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or parkinson disease.
      ). A 2014 study evaluated the effect or progressive RT on improving the functional capacity of RRMS patients aged from 18 to 60 years, and with EDSS from 2 to 4. Duration of the intervention was 24 weeks, followed by an additional 24 weeks of unsupervised exercise to assess if any improvements were maintained. The training protocol consisted of progressive weights of decreasing repetitions (reps) of four lower-body exercises: leg press, hip flexion, leg extension, prone hamstring curl, and two upper-body exercises: cable pull-down and cable triceps extension. Functional outcomes were significantly improved and they include timed 25 ft. walk test (T25FWT) (p < 0.01), 2MWT (p < 0.01), 5STS (p < 0.001), and stair climb (p < 0.001), compared to baseline. 15 out of 17 participants reported that they carried on with the self-guided RT and managed to maintain their improvements upon follow up (
      • Kjølhede T.
      • Vissing K.
      • de Place L.
      • Pedersen B.G.
      • Ringgaard S.
      • Stenager E.
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      ).
      • Dalgas U.
      • Stenager E.
      • Jakobsen J.
      • Petersen T.
      • Hansen H.J.
      • Knudsen C.
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      studied the effect of lower extremity progressive RT on muscle strength and functional capacity of MS patients. This randomised controlled trial (RCT) included 38 patients equally divided into a control and intervention group, where the moderately impaired MS patients completed a 12-week lower body RT program. Patient EDSS ranged from 3 to 5.5 and 15 patients completed the program. Exercises in the protocol included leg press, knee extension, hip flexion, hamstring curl, and hip extension, performed at a fast concentric phase and a slow eccentric phase. The load was progressively increased by decreasing the number of reps and increasing weight over the 12-week duration. Although this intervention did not affect the EDSS of patients, improvements were seen in the knee extension, knee flexion, and leg press maximum voluntary contraction (MVC) (p < 0.05) compared to the control group. All functional scores including chair-stand test (CST), stair-climb, and 6MWT also improved compared to the control group (p < 0.05). Moreover, a pilot study examined the effect of a 12-week program of combined high-intensity interval training (HIIT) and RT on MS patients. It included 30 MS patients with EDSS between 0 and 5 and no relapses in the previous month. Endurance sessions were conducted using a bike ergometer. During the first 4 weeks, RT consisted of body weight exercises for quadriceps and hamstrings, and workload was thereafter progressively increased by increasing the number of reps performed. Compared to the control group, the intervention group demonstrated improvements in physical capacity including increased muscle strength in the quadriceps (p < 0.001) and hamstrings (p < 0.05), as well as many aspects of the QoL such as vitality (p = 0.005), general well-being (p = 0.0195), and physical health composite (p = 0.034) (
      • Zaenker P.
      • Favret F.
      • Lonsdorfer E.
      • Muff G.
      • de Seze J.
      • Isner-Horobeti M.E.
      High-intensity interval training combined with resistance training improves physiological capacities, strength and quality of life in multiple sclerosis patients: a pilot study.
      ).
      In another randomized controlled trial, a 24-week strength training program combined with cognitive motor tasks has shown significant improvements in the interventional group compared to the control group. This RCT included 15 patients in the exercise group, with an average EDSS of 3.6. The training program targeted 4 abilities: static strength abilities, bodyweight exercises, dynamic strength training using machines, elastic bands, or manual resistance training, and finally, walking and/or running. Exercise progression was controlled by increasing the number of reps when applicable. Improvements were seen in the STS (p < 0.01), peak force (p < 0.01), and balance (p < 0.05) (
      • Gutiérrez-Cruz C.
      • Rojas-Ruiz F.J.
      • de la Cruz-Márquez J.C.
      • Gutiérrez-Dávila M.
      Effect of a combined program of strength and dual cognitive-motor tasks in multiple sclerosis subjects.
      ). Another clinical trial studied the effect of a short exercise intervention on MS patients, where one group performed endurance workouts and the other performed a program of combined endurance and RT workouts. This study included MS patients aged 18–65 with an average EDSS of 2.6. Exercise sessions were done twice weekly with a duration of 40 min each, and the total duration of the intervention was 3 months. 19 out of 30 patients completed the protocol, where both groups showed an increase in aerobic threshold (p < 0.01) and maximum force of extension of both the right knee and shoulder (p < 0.01) (
      • Kerling A.
      • Keweloh K.
      • Tegtbur U.
      • Kück M.
      • Grams L.
      • Horstmann H.
      • et al.
      Effects of a short physical exercise intervention on patients with multiple sclerosis (MS).
      ). Additionally, a randomized controlled trial was carried out in 2015 in which 34 MS patients with an average EDSS of 2.3 were divided into 3 groups, 2 of which performed a program of RT combined with either HIIT or high-intensity cardiovascular training (HICT). The intervention consisted of 5 sessions/week. HIIT was carried out in the form of high-intensity cycle interval training, with progression by increasing work time and maintaining the same rest time, as well as increasing the percentage of maximum heart rate (HR) during the exercise. HICT consisted of cycling and treadmill walking or running. Progression was done by increasing work time at 80–90% of maximum HR. In both groups, RT consisted of moderate-high intensity unilateral lower body exercises (leg press, leg curl, hip extension) as well as arm and chest press. Muscle fiber size increased in both training groups after 12 weeks (p < 0.05 in both groups) compared to the control group. Moreover, strength of knee flexion and knee extension significantly increased in both groups (p = 0.01 and p = 0.006, respectively) compared to the control group. Endurance (p < 0.05) and physical activity (p < 0.005) increased in both groups as well (
      • Wens I.
      • Dalgas U.
      • Vandenabeele F.
      • Grevendonk L.
      • Verboven K.
      • Hansen D.
      • et al.
      High intensity exercise in multiple sclerosis: effects on muscle contractile characteristics and exercise capacity, a randomised controlled trial.
      ).
      The effects of RT on female MS patients were examined in different clinical trials; the first one investigated the effect of a 12-week combined RT and endurance training program on muscle strength, fatigue, depression, and quality of life (QoL). 14 out of 37 RRMS patients with EDSS < 4, mild-moderate severity, and aged between 18 and 60 were allocated in the intervention group. Training sessions consisted of 25 min aerobic training at a moderate-vigorous intensity, followed by RT. RT consisted of calisthenics, dumbbell and elastic band exercises targeting major muscle groups, performed at 8–12 reps each, and progressively increasing in load when performing 12 reps becomes easy. Improvements were seen in the MVC (p < 0.01), fatigue (p < 0.01), depression (p < 0.01), mental and physical QoL (p < 0.05) compared to baseline. Significant improvement versus baseline was maintained after 12 weeks of detraining only for fatigue (p < 0.05) (
      • Correale L.
      • Buzzachera C.F.
      • Liberali G.
      • Codrons E.
      • Mallucci G.
      • Vandoni M.
      • et al.
      Effects of combined endurance and resistance training in women with multiple sclerosis: a randomized controlled study.
      ). The second study involved 12 female RRMS patients in the intervention group with EDSS between 2 and 4. The 8-week RT program consisted of 3 sets of 5–12 reps of knee extension, pec deck fly, and lat pulldowns. This was followed by six movements on a vibration plate: squats, deep squats, deep lunges, sitting forward bend, gentle push-ups, and calf massage. Improvements in the force of knee extensors, scapula abduction, scapula downward rotation were seen compared to the control group (p < 0.001). Moreover, right (p = 0.02) and left (p < 0.001) leg balance, as well as 10MWT (p < 0.001) were improved (
      • Eftekhari E.
      • Mostahfezian M.
      • Etemadifar M.
      • Zafari A.
      Resistance training and vibration improve muscle strength and functional capacity in female patients with multiple sclerosis.
      ).
      Dodd et al. examined the effect of RT on 36 RRMS patients who were allocated in a progressive RT program for 10 weeks. These patients were at least 18 years old, with mild-moderate walking disabilities. RT consisted of leg press, knee extension, calf raise, leg curl, and reverse leg press. At the end of the intervention, 1 repetition-maximum (1RM) leg press significantly increased (CI 4.9–16.7), as well as 1RM reverse leg press (CI 1.9–9.5) compared to control. Moreover, fatigue decreased (CI −6.6 - −1.3) and physical QoL increased (CI 0.1–2.9) compared to control (
      • Dodd K.
      • Taylor N.
      • Shields N.
      • Prasad D.
      • McDonald E.
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      ).
      • Dalgas U.
      • Stenager E.
      • Jakobsen J.
      • Petersen T.
      • Hansen H.
      • Knudsen C.
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      also studied the effects of a 12-week progressive RT program on the fatigue and QoL of 19 RRMS patients, with EDSS between 3 and 5.5, mild-moderate disability, and at least 18 years of age. The progressive RT program consisted of lower body exercises (leg press, knee extension, hip flexion, hamstring curl, and hip extension) performed at a fast concentric phase and a slow eccentric phase. For the first 2 weeks, 3 sets of each movement were performed for 10 reps. Over the weeks, the number of reps were decreased with increasing load until the final 2 weeks, where the participants performed 3 sets of 8 reps at the highest load. Fatigue (p = 0.04), mood (p = 0.01), and QoL (p < 0.05) were reportedly improved compared to the control group.
      A study involving 20 male MS patients examined the effect of an 8-week progressive RT program on the motor function, muscle strength, balance, and disease progression of the participants. Patients’ EDSS ranged from 1 to 6, and they were randomized into either the exercise or control group. Weight machines were used for lower and upper body exercises, including leg extension, leg and chest press, and seated row. Starting from 6 to 10 reps at 1RM (determined at baseline) during the first week, subjects performed progressively heavier sets of 10–15 reps at 60, 70, and 80% during each of the subsequent weeks. When 15 reps at 80% became too easy, subjects increased the load by 2–5% in the following sessions. At the end of the 8 weeks, participants in the exercise group showed an improvement in the motor function as assessed by the 10MWT, 3 min step test, and timed up and go (TUG) test (p = 0.006 for all tests compared to baseline). Measurements of muscle strength as assessed by seated row, chest press, leg extension and leg press, also all improved compared to baseline (p = 0.006). There was no statistically significant improvement in balance, but EDSS of patients in the control group significantly decreased (p = 0.037) compared to baseline (
      • Moradi M.
      • Sahraian M.A.
      • Aghsaie A.
      • Kordi M.R.
      • Meysamie A.
      • Abolhasani M.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      ).
      Another study attempted to establish a widely applicable and convenient strength training protocol for MS using minimal equipment (only resistance bands with varying degrees of resistance), that is ideally well suited for patients with different degrees of disability. 26 patients were recruited in this progressive RT program, with their EDSS falling between 1 and 6.5, and their ages between 23 and 65 years. Exercises were lower-body oriented, including hip flexion, hip abduction, hip extension, knee flexion, hip external rotation, and knee extension, all performed with a resistance band. The training protocol ended with a functional exercise workout. Hip strength improved after 12 weeks (p < 0.005), and improvement in hip flexion was seen as early as 8 weeks (p = 0.013) (
      • Keller J.L.
      • Fritz N.
      • Chiang C.C.
      • Jiang A.
      • Thompson T.
      • Cornet N.
      • et al.
      Adapted resistance training improves strength in eight weeks in individuals with multiple sclerosis.
      ). A slightly longer duration of 10 weeks was used where 30 RRMS and SPMS patients with EDSS between 1 and 6 were randomly allocated in a RT group or a control group. RT group participants performed 10 weeks of lower-extremity fast-concentric phase RT (FVCRT). Subjects performed 4 lower-limb exercises (leg press, leg extension, hip extension, and seated calf raises) for 2–4 sets of 8–15 reps at 60–75% 1RM. However, at the end of the intervention, no significant difference was found in the balance of the RT group compared to the control group (
      • Andreu-Caravaca L.
      • Ramos-Campo D.J.
      • Chung L.H.
      • Rubio-Arias J.Á.
      Can strength training modify voluntary activation, contractile properties and spasticity in Multiple Sclerosis?: a randomized controlled trial.
      ).
      On evaluating the effects of maximal RT (defined as RT using up to 90% 1 RM) in MS patients, Gomez-Illan et al. conducted a study involving 13 RRMS patients with an average EDSS of 2.58 and an average age of 43.7 years. Weekly training consisted of a conditioning phase for the first 4 weeks, carried out at 50–60% of 1RM performed for 2 sets of 8–10 or 12–14 reps. From weeks 8 through 12, 3–5 sets of 4–7 reps were performed at 75–90% of 1RM. Exercises performed included shoulder press, lat pulldown, leg extension, leg curl, among many others, listed in full detail in the appendix of the original article. The maximal strength training group showed statistically significant improvements in all parameters including quadriceps and hamstring strength (p < 0.001), fatigue score (p < 0.001), and TUG test (p < 0.001) compared to baseline (
      • Gomez-Illan R.
      • Reina R.
      • Barbado D.
      • Sabido R.
      • Moreno-Navarro P.
      • Roldan A
      Effects of maximal strength training on perceived-fatigue and functional mobility in persons with relapsing-remitting multiple sclerosis.
      ).
      Finally, a study investigated the effect of progressive RT on the strength and fatigue of 14 RRMS patients with EDSS < 4, mediated through metabolic changes. Participants underwent a 12-week hip strengthening intervention using a progressive RT approach following the protocol published in (
      • Keller J.L.
      • Fritz N.
      • Chiang C.C.
      • Jiang A.
      • Thompson T.
      • Cornet N.
      • et al.
      Adapted resistance training improves strength in eight weeks in individuals with multiple sclerosis.
      ). Patients completing the study demonstrated improvements in hip strength (p = 0.008), 6MWT (p = 0.01), T25FW (p = 0.008), and fatigue (p = 0.0056) (
      • Keller J.
      • Zackowski K.
      • Kim S.
      • Chidobem I.
      • Smith M.
      • Farhadi F.
      • et al.
      Exercise leads to metabolic changes associated with improved strength and fatigue in people with MS.
      ), although a 2015 RCT concluded that treadmill walking may be a more favourable approach to improve walking in patients with mild-moderate MS (
      • Braendvik S.M.
      • Koret T.
      • Helbostad J.L.
      • Lorås H.
      • Bråthen G.
      • Hovdal H.O.
      • et al.
      Treadmill training or progressive strength training to improve walking in people with multiple sclerosis? A randomized parallel group trial.
      ). These studies and their outcomes are summarized in Table 1.
      Table 1Summary of the different RT-based interventions in MS patients. RT: resistance training; PRT: progressive resistance training; EDSS: estimated disability status score; MWT: minute walk test; STS: sitting-to-standing; TUG: timed-up-and-go; QoL: quality of life; T25FWT: timed 25 feet walk test; MVC: maximum velocity of contraction; CST: chair-stand test; HIIT: high intensity interval training; HICT: high intensity cardiovascular training; ST: strength training.
      StudyInterventionEDSSDurationOutcome (p value)
      p value or confidence interval.
      (
      • Taul-Madsen L.
      • Connolly L.
      • Dennett R.
      • Freeman J.
      • Dalgas U.
      • Hvid L.G.
      Is aerobic or resistance training the most effective exercise modality for improving lower extremity physical function and perceived fatigue in people with multiple sclerosis? a systematic review and meta-analysis.
      )
      PRT/body-weight/absolute weights1.5–78–24 weeksMuscle strength (p = 0.013)

      Short walk (p = 0.006)

      Long walk (p < 0.05)

      2MWT (p < 0.05)

      5STS (p < 0.05)

      Stair climb (p < 0.05)

      3 min step test (p < 0.05)

      TUG (p < 0.05)
      (
      • Cruickshank T.M.
      • Reyes A.R.
      • Ziman M.R.
      A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or parkinson disease.
      )
      Lower body/machine exercises/weighted vest/home-based RT1–6.53–6 monthsMuscle strength (p = 0.005)

      Fatigue (p < 0.05)

      Functional capacity (p < 0.05)

      QoL (p < 0.05)

      Muscle power (p < 0.05)
      (
      • Kjølhede T.
      • Vissing K.
      • de Place L.
      • Pedersen B.G.
      • Ringgaard S.
      • Stenager E.
      • et al.
      Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up.
      )
      PRT: leg press/hip flexion/leg extension/hamstring curl/cable pulldown/cable tricep extension2–424 weeksT25FWT (p < 0.01)

      2MWT (p < 0.01)

      5STS (p < 0.01)

      Stair climb (p < 0.01)
      (
      • Dalgas U.
      • Stenager E.
      • Jakobsen J.
      • Petersen T.
      • Hansen H.J.
      • Knudsen C.
      • et al.
      Resistance training improves muscle strength and functional capacity in multiple sclerosis.
      )
      PRT: leg press/knee extension/hip flexion/hamstring curl/hip extension

      Performed at slow eccentric phase
      3–5.512 weeksMVC (p < 0.05)

      CST (p < 0.05)

      Stair climb (p < 0.05)

      6MWT (p < 0.05)
      (
      • Zaenker P.
      • Favret F.
      • Lonsdorfer E.
      • Muff G.
      • de Seze J.
      • Isner-Horobeti M.E.
      High-intensity interval training combined with resistance training improves physiological capacities, strength and quality of life in multiple sclerosis patients: a pilot study.
      )
      HIIT + RT: body weight for 4 weeks, then increase number of reps0–512 weeksMuscle strength (p < 0.01)

      QoL (p < 0.05)
      (
      • Gutiérrez-Cruz C.
      • Rojas-Ruiz F.J.
      • de la Cruz-Márquez J.C.
      • Gutiérrez-Dávila M.
      Effect of a combined program of strength and dual cognitive-motor tasks in multiple sclerosis subjects.
      )
      Static and dynamic ST/body weight/walking/running3.624 weeksSTS (p < 0.01)

      Muscle peak force (p < 0.01)

      Balance (p < 0.05)
      (
      • Kerling A.
      • Keweloh K.
      • Tegtbur U.
      • Kück M.
      • Grams L.
      • Horstmann H.
      • et al.
      Effects of a short physical exercise intervention on patients with multiple sclerosis (MS).
      )
      Endurance + RT2.63 monthsAerobic threshold (p < 0.01)

      Maximum force of extension (p < 0.01)
      (
      • Wens I.
      • Dalgas U.
      • Vandenabeele F.
      • Grevendonk L.
      • Verboven K.
      • Hansen D.
      • et al.
      High intensity exercise in multiple sclerosis: effects on muscle contractile characteristics and exercise capacity, a randomised controlled trial.
      )
      RT + (HIIT/HICT): RT was moderate to high intensity exercises (leg press/leg curl/hip extension/arm press/chest press)2.312 weeksMuscle fiber size (p < 0.05)

      Knee flexion (p < 0.01) and extension (p < 0.01)

      Muscle strength (p = 0.006)

      Endurance (p < 0.05)

      Physical activity (p < 0.05)
      (
      • Correale L.
      • Buzzachera C.F.
      • Liberali G.
      • Codrons E.
      • Mallucci G.
      • Vandoni M.
      • et al.
      Effects of combined endurance and resistance training in women with multiple sclerosis: a randomized controlled study.
      )
      Endurance + PRT in the form of calisthenics/dumbbell exercises/elastic bands<412 weeksMVC (p < 0.01)

      Fatigue (p < 0.01)

      Depression (p < 0.01)

      QoL (p < 0.05)
      (
      • Eftekhari E.
      • Mostahfezian M.
      • Etemadifar M.
      • Zafari A.
      Resistance training and vibration improve muscle strength and functional capacity in female patients with multiple sclerosis.
      )
      Knee extension/pec deck fly/lat pulldown + on vibration plate: squats/lunges/forward bend/pushups/calf massage2–48 weeksMVC knee (<0.001)

      MVC scapula (p < 0.001)

      Right (p < 0.02) and left (p < 0.001) leg balance

      10MWT (p < 0.001)
      (
      • Dodd K.
      • Taylor N.
      • Shields N.
      • Prasad D.
      • McDonald E.
      • Gillon A.
      Progressive resistance training did not improve walking but can improve muscle performance, quality of life and fatigue in adults with multiple sclerosis: a randomized controlled trial.
      )
      PRT: leg press/knee extension/calf raise/leg curl/reverse leg pressMild-moderate10 weeks1RM leg press (4.9–16.7)

      1RM reverse leg press (1.9–9.5)

      Fatigue (−6.6- −1.3)

      QoL (0.1–2.9)
      (
      • Dalgas U.
      • Stenager E.
      • Jakobsen J.
      • Petersen T.
      • Hansen H.
      • Knudsen C.
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      )
      PRT: leg press/knee extension/hip flexion/hamstring curl/hip extension performed at a slow eccentric phase3–5.512 weeksFatigue (p = 0.04)

      Mood (p = 0.01)

      QoL (p < 0.05)
      (
      • Moradi M.
      • Sahraian M.A.
      • Aghsaie A.
      • Kordi M.R.
      • Meysamie A.
      • Abolhasani M.
      Effects of eight-week resistance training program in men with multiple sclerosis.
      )
      PRT: leg extension/leg press/chest press/seated row1–68 weeks10MWT (p = 0.006)

      3 min step tets (p = 0.006)

      TUG (p = 0.006)

      Muscle strength (p = 0.006)

      EDSS (p = 0.037)
      (
      • Keller J.L.
      • Fritz N.
      • Chiang C.C.
      • Jiang A.
      • Thompson T.
      • Cornet N.
      • et al.
      Adapted resistance training improves strength in eight weeks in individuals with multiple sclerosis.
      )
      PRT using resistance bands: hip flexion/hip abduction/hip extension/knee flexion/hip extension/knee extension + functional workout1–6.512 weeksHip strength (p<0.005)

      Hip flexion (p = 0.013)
      (
      • Gomez-Illan R.
      • Reina R.
      • Barbado D.
      • Sabido R.
      • Moreno-Navarro P.
      • Roldan A
      Effects of maximal strength training on perceived-fatigue and functional mobility in persons with relapsing-remitting multiple sclerosis.
      )
      PRT: shoulder press/lat pulldown/leg extension/leg curl/other isolation movements2.5812 weeksMuscle strength (p < 0.001)

      Fatigue (p < 0.001)

      TUG (p < 0.001)
      (
      • Keller J.
      • Zackowski K.
      • Kim S.
      • Chidobem I.
      • Smith M.
      • Farhadi F.
      • et al.
      Exercise leads to metabolic changes associated with improved strength and fatigue in people with MS.
      )
      PRT protocol in (
      • Dalgas U.
      • Stenager E.
      • Jakobsen J.
      • Petersen T.
      • Hansen H.
      • Knudsen C.
      • et al.
      Fatigue, mood and quality of life improve in MS patients after progressive resistance training.
      )
      <412 weeksHip strength (p = 0.008)

      6MWT (p = 0.01)

      T25FWT (p = 0.008)

      Fatigue (p = 0.0056)
      low asterisk p value or confidence interval.
      The demonstrated relatively well-established evidence corroborating the beneficial effects of incorporating RT in the lifestyles of MS patients prompted the in-depth investigation of the molecular mechanisms underlying these positive outcomes, with a particular interest and focus on how RT affects various components of the immune system in individuals in general, followed by a focus on the changes ensuing in MS patients in particular.

      3. Resistance training alters the immune system

      Ample literature has previously investigated the molecular effects of different exercise modalities, including RT, on components and key players of the immune system. A randomized controlled trial conducted in 2020 showed that the kynurenine (KYN) pathway components are altered following an acute RT intervention (
      • Joisten N.
      • et al.
      Exercise and the Kynurenine pathway: current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training.
      ). The KYN pathway is dysregulated in several chronic diseases (
      • Vancassel S.
      • Capuron L.
      • Castanon N.
      Brain kynurenine and BH4 pathways: relevance to the pathophysiology and treatment of inflammation-driven depressive symptoms.
      ;
      • Arnone D.
      • Saraykar S.
      • Salem H.
      • Teixeira A.L.
      • Dantzer R.
      • Selvaraj S.
      Role of Kynurenine pathway and its metabolites in mood disorders: a systematic review and meta-analysis of clinical studies.
      ), and its metabolites exhibit neuro- and immune-modulatory properties (
      • Chung D.J.
      • Rossi M.
      • Romano E.
      • Ghith J.
      • Yuan J.
      • Munn D.H.
      • et al.
      Indoleamine 2,3-dioxygenase–expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells.
      ;
      • Munn D.H.
      • Shafizadeh E.
      • Attwood J.T.
      • Bondarev I.
      • Pashine A.
      • Mellor A.L.
      Inhibition of T Cell Proliferation by Macrophage Tryptophan Catabolism.
      ;
      • Munn D.H.
      • Mellor A.L.
      Indoleamine 2,3 dioxygenase and metabolic control of immune responses.
      ;
      • Mándi Y.
      • Vécsei L.
      The kynurenine system and immunoregulation.
      ). KYN/tryptophan (TRP) ratio was increased in the serum of patients following acute RT intervention immediately after exercise (p = 0.041), and declined to baseline levels after one hour (p = 0.005 VS post exercise). Although an elevated KYN/TRP ratio has been consistently associated with an exacerbation of inflammation and neurotoxicity, patients with inflammation-mediated disorders may potentially benefit from short-term or transient increases in serum levels of KYN (
      • Lim C.K.
      • Bilgin A.
      • Lovejoy D.B.
      • Tan V.
      • Bustamante S.
      • Taylor B v.
      • et al.
      Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression.
      ).
      RT also appears to modulate the levels of various cytokines, including interleukin (IL)−10, IL-15, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), C-C chemokine ligand-2 (CCL2), as well as brain-derived neurotrophic factor (BDNF). RT was associated with an increase in the serum levels of IL-10 (p = 0.004) (
      • Kazemi F.
      The correlation of resistance exercise-induced myostatin with insulin resistance and plasma cytokines in healthy young men.
      ), serum IL-15 (p < 0.01) (
      • Pérez-López A.
      • McKendry J.
      • Martin-Rincon M.
      • Morales-Alamo D.
      • Pérez-Köhler B.
      • Valadés D.
      • et al.
      Skeletal muscle <scp>IL</scp>-15/<scp>IL</scp>-15Rα and myofibrillar protein synthesis after resistance exercise.
      ;
      • Bazgir B.
      • Salesi M.
      • Koushki M.
      • Amirghofran Z.
      Effects of eccentric and concentric emphasized resistance exercise on il-15 serum levels and its relation to inflammatory markers in athletes and non-athletes.
      ;
      • Kapilevich L.V.
      • Zakharova A.N.
      • Kabachkova A.V.
      • Kironenko T.A.
      • Orlov S.N
      Dynamic and static exercises differentially affect plasma cytokine content in elite endurance- and strength-trained athletes and untrained volunteers.
      ), although reported not significantly increased in (
      • Oliver J.
      • Jenke S.
      • Mata J.
      • Kreutzer A.
      • Jones M.
      Acute effect of cluster and traditional set configurations on myokines associated with hypertrophy.
      ), and serum BDNF immediately post-RT (p < 0.05) (
      • Yarrow J.F.
      • White L.J.
      • McCoy S.C.
      • Borst S.E.
      Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF).
      ) and (p = 0.0147) (
      • Fortunato A.K.
      • Pontes W.M.
      • de Souza D.M.S.
      • Prazeres J.S.F.
      • Marcucci-Barbosa L.S.
      • Santos J.M.M.
      • et al.
      Strength training session induces important changes on physiological, immunological, and inflammatory biomarkers.
      ), as well as immediately post (p = 0.001), 30 min after (p < 0.001), and 60 min after RT (p < 0.001) (
      • Church D.D.
      • Hoffman J.R.
      • Mangine G.T.
      • Jajtner A.R.
      • Townsend J.R.
      • Beyer K.S.
      • et al.
      Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise.
      ). These studies used different formats for weight-training, with different emphases on the eccentric phase.
      • Kapilevich L.V.
      • Zakharova A.N.
      • Kabachkova A.V.
      • Kironenko T.A.
      • Orlov S.N
      Dynamic and static exercises differentially affect plasma cytokine content in elite endurance- and strength-trained athletes and untrained volunteers.
      using static hold at a weight corresponding to 50% of 1RM deadlift, additionally demonstrated that weight-trained individuals have a lower baseline of serum IL-6 compared to controls (p < 0.01); IL-6 increased following RT (p < 0.01), although this increase was nearly 2-folds less than that seen in controls or endurance athletes. An increase in IL-8 was noted immediately following RT, but significantly declined below baseline 30 min post-exercise (p < 0.05). A study also reported that a progressive, 19-week long RT carried out at 60–85% of 1RM, combined with patient education regarding dietary advice reduced the serum levels of CCL2 (p = 0.01) and leptin (p < 0.01) (
      • Lopes L.M.P.
      • Oliveira E.C.D.
      • Becker L.K.
      • Costa G.D.P.
      • Pinto K.M.D.C.
      • Talvani A.
      • et al.
      Resistance training associated with dietetic advice reduces inflammatory biomarkers in the elderly.
      ).
      In an 8-week randomized controlled trial, patients undergoing RT showed enhanced autophagy as evident by the increase in some autophagy-related genes (p62/SQSTM1, Atg12, Atg16, all with p-values < 0.05), reduced NLRP3 inflammasome activation (p < 0.03), and reduced apoptotic proteins (p < 0.05) in peripheral blood mononuclear cells (PBMCs) in elderly subjects (
      • Mejías-Peña Y.
      • Estébanez B.
      • Rodriguez-Miguelez P.
      • Fernandez-Gonzalo R.
      • Almar M.
      • de Paz J.A.
      • et al.
      Impact of resistance training on the autophagy-inflammation-apoptosis crosstalk in elderly subjects.
      ). Additionally, Quiroga R et al. demonstrated the association of combined endurance and progressive RT using isolation movements (including leg press, knee extension) with a decrease of NLRP3 inflammasome (p < 0.05) in 25 obese children (
      • Quiroga R.
      • Nistal E.
      • Estébanez B.
      • Porras D.
      • Juárez-Fernández M.
      • Martínez-Flórez S.
      • et al.
      Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children.
      ). Another 6-week randomized controlled trial used a combined endurance and RT regimen consisting of 20 min endurance training followed by 6 machine-supported exercises (upper- and lower-extremity oriented). Outcomes demonstrated increased CD4+/CD8+ ratios (p = 0.021), systemic decrease in each of IL-6 (p = 0.008), IL-8 (p = 0.003), IL-10 (p = 0.024), and vascular endothelial growth factor (VEGF) (p = 0.021) levels in the interventional group (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      ), suggesting that this type of training may stimulate the immune system. Conversely, yet another study reported an increase in serum IL-10 following an elastic-band based 28-week RT program in 16 patients over the age of 60 (
      • Chupel M.U.
      • Direito F.
      • Furtado G.E.
      • Minuzzi L.G.
      • Pedrosa F.M.
      • Colado J.C.
      • et al.
      Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment.
      ).
      In 28 women with an average age of 70.6 years, long-term (average of 8.6 months) RT has been associated with a higher phagocytic activity (p < 0.001) of neutrophils, lower levels of serum TNF-α (p = 0.036), and lower levels of serum IL-6 (p = 0.002) (
      • Bartholomeu-Neto J.
      • Brito C.J.
      • Nóbrega O.T.
      • Sousa V.C.
      • Oliveira Toledo J.
      • Silva Paula R.
      • et al.
      Adaptation to resistance training is associated with higher phagocytic (but not oxidative) activity in neutrophils of older women.
      ). Similarly, 24 weeks of resistance training twice weekly has been associated with reduced serum expression of cell-surface toll-like receptor-4 (TLR4) in older women (65,80 years), compared to non-active subjects (p < 0.05) (
      • Mcfarlin B.K.
      • Flynn M.G.
      • Campbell W.W.
      • Stewart L.K.
      • Timmerman K.L
      TLR4 is lower in resistance-trained older women and related to inflammatory cytokines.
      ). Another randomized controlled trial of elderly subjects (average age of 65 years) investigating expression changes in TLRs, showed that an 8-week strength program including progressive loads of isolation movements (leg press, peck deck) managed to downregulate PBMC cell-surface levels of TLR2 and TLR4 in trained versus untrained individuals (p < 0.05 for both), suggesting that RT may be useful for attenuating proinflammatory TLR signaling pathway and modulating immune system activity (
      • Rodriguez-Miguelez P.
      • Fernandez-Gonzalo R.
      • Almar M.
      • Mejías Y.
      • Rivas A.
      • de Paz J.A.
      • et al.
      Role of toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects.
      ).
      The increased muscle energy demand and breakdown after RT is followed by the activation of the endogenous antioxidant system (EAS). This bout of oxidative stress also impacts signaling pathways such as nuclear factor kappa-B (NF-kB) and mitogen activated kinase (MAPK), and activation of these pathways triggers the antioxidant response of mitochondrial superoxide dismutase (SOD) (
      • Bartholomeu-Neto J.
      • Brito C.J.
      • Nóbrega O.T.
      • Sousa V.C.
      • Oliveira Toledo J.
      • Silva Paula R.
      • et al.
      Adaptation to resistance training is associated with higher phagocytic (but not oxidative) activity in neutrophils of older women.
      ). A 3x weekly 3-month intervention of RT in older women (at least 65 years) caused a significant (p < 0.05) upregulation of several anti-inflammatory genes, including histamine receptor H1 (HRH1), IL-4, fibroblast growth factor-21 (FGF21), aryl hydrocarbon receptor nuclear translocator-2 (ARNT2), superoxide dismutase-2 (SOD2), IL-9, among others (
      • Liberman K.
      • Njemini R.
      • Forti L.N.
      • Cools W.
      • Debacq-Chainiaux F.
      • Kooijman R.
      • et al.
      Three months of strength training changes the gene expression of inflammation-related genes in PBMC of older women: a randomized controlled trial.
      ). Table 2 summarizes the different cytokines that have been reported across literature to be altered following RT programs.
      Table 2Cytokines with differential expression following RT programs. RT: resistance training; IL: interleukin; BDNF: brain-derived neurotrophic factor; TNF: tumor necrosis factor; CCL: C-C chemokine ligand; VEGF: vascular endothelial growth factor; TLR: toll-like receptor; KYN/TRP: kynurenine/tryptophan.
      Altered componentExpression change (reference)
      IL-10↑ (
      • Kazemi F.
      The correlation of resistance exercise-induced myostatin with insulin resistance and plasma cytokines in healthy young men.
      ;
      • Chupel M.U.
      • Direito F.
      • Furtado G.E.
      • Minuzzi L.G.
      • Pedrosa F.M.
      • Colado J.C.
      • et al.
      Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment.
      )

      ↓ (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )
      IL-15↑ (
      • Bazgir B.
      • Salesi M.
      • Koushki M.
      • Amirghofran Z.
      Effects of eccentric and concentric emphasized resistance exercise on il-15 serum levels and its relation to inflammatory markers in athletes and non-athletes.
      ;
      • Kapilevich L.V.
      • Zakharova A.N.
      • Kabachkova A.V.
      • Kironenko T.A.
      • Orlov S.N
      Dynamic and static exercises differentially affect plasma cytokine content in elite endurance- and strength-trained athletes and untrained volunteers.
      ;
      • Oliver J.
      • Jenke S.
      • Mata J.
      • Kreutzer A.
      • Jones M.
      Acute effect of cluster and traditional set configurations on myokines associated with hypertrophy.
      )
      BDNF↑ (
      • Yarrow J.F.
      • White L.J.
      • McCoy S.C.
      • Borst S.E.
      Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF).
      ;
      • Fortunato A.K.
      • Pontes W.M.
      • de Souza D.M.S.
      • Prazeres J.S.F.
      • Marcucci-Barbosa L.S.
      • Santos J.M.M.
      • et al.
      Strength training session induces important changes on physiological, immunological, and inflammatory biomarkers.
      ;
      • Church D.D.
      • Hoffman J.R.
      • Mangine G.T.
      • Jajtner A.R.
      • Townsend J.R.
      • Beyer K.S.
      • et al.
      Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise.
      )
      IL-6↑ (
      • Kapilevich L.V.
      • Zakharova A.N.
      • Kabachkova A.V.
      • Kironenko T.A.
      • Orlov S.N
      Dynamic and static exercises differentially affect plasma cytokine content in elite endurance- and strength-trained athletes and untrained volunteers.
      )

      ↓ (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      ;
      • Bartholomeu-Neto J.
      • Brito C.J.
      • Nóbrega O.T.
      • Sousa V.C.
      • Oliveira Toledo J.
      • Silva Paula R.
      • et al.
      Adaptation to resistance training is associated with higher phagocytic (but not oxidative) activity in neutrophils of older women.
      )
      IL-8↓ (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )
      TNF-α↓ (
      • Bazgir B.
      • Salesi M.
      • Koushki M.
      • Amirghofran Z.
      Effects of eccentric and concentric emphasized resistance exercise on il-15 serum levels and its relation to inflammatory markers in athletes and non-athletes.
      ;
      • Chupel M.U.
      • Direito F.
      • Furtado G.E.
      • Minuzzi L.G.
      • Pedrosa F.M.
      • Colado J.C.
      • et al.
      Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment.
      ;
      • Bartholomeu-Neto J.
      • Brito C.J.
      • Nóbrega O.T.
      • Sousa V.C.
      • Oliveira Toledo J.
      • Silva Paula R.
      • et al.
      Adaptation to resistance training is associated with higher phagocytic (but not oxidative) activity in neutrophils of older women.
      )
      CCL2↓ (
      • Lopes L.M.P.
      • Oliveira E.C.D.
      • Becker L.K.
      • Costa G.D.P.
      • Pinto K.M.D.C.
      • Talvani A.
      • et al.
      Resistance training associated with dietetic advice reduces inflammatory biomarkers in the elderly.
      )
      Leptin↓ (
      • Lopes L.M.P.
      • Oliveira E.C.D.
      • Becker L.K.
      • Costa G.D.P.
      • Pinto K.M.D.C.
      • Talvani A.
      • et al.
      Resistance training associated with dietetic advice reduces inflammatory biomarkers in the elderly.
      )
      VEGF↓ (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )
      TLR↓ (
      • Mcfarlin B.K.
      • Flynn M.G.
      • Campbell W.W.
      • Stewart L.K.
      • Timmerman K.L
      TLR4 is lower in resistance-trained older women and related to inflammatory cytokines.
      ;
      • Rodriguez-Miguelez P.
      • Fernandez-Gonzalo R.
      • Almar M.
      • Mejías Y.
      • Rivas A.
      • de Paz J.A.
      • et al.
      Role of toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects.
      ;
      • Wu Y.
      • Hu X.
      • Chen L.
      Chronic resistance exercise improves functioning and reduces toll-like receptor signaling in elderly patients with postoperative deconditioning.
      )
      KYN/TRP ratioAcute ↑ (
      • Joisten N.
      • et al.
      Exercise and the Kynurenine pathway: current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training.
      )
      Numerous inflammatory mediators and cytokines have been unequivocally reported to be dysregulated in the sera/cerebrospinal fluid (CSF) of MS patients, including the aforementioned key players of the immune system. In order to gain a better understanding of the correlation between the effect of RT on the immune system and the potential extension of this beneficial effect to MS patients, the roles of these cytokines in MS will be briefly reviewed in the following section.

      4. Resistance training-associated differentially expressed inflammatory key players in multiple sclerosis pathology

      Before any conclusions can be formed regarding how RT may affect the immune system in MS patients, understanding the roles of the aforementioned cytokines, whose expression levels are altered following RT, in MS is pivotal. Although widely established, it is worth noting that an altered permeability of BBB is one of the hallmarks and essential components of the disease, which allows peripheral cytokine expression profiles to be, to a great extent, mirrored inside the CNS (
      • Cramer S.P.
      • Simonsen H.
      • Frederiksen J.L.
      • Rostrup E.
      • Larsson H.B.W.
      Abnormal blood–brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI.
      ).

      4.1 Anti-inflammatory/neuroprotective mediators

      4.1.1 IL-10

      First, conflicting evidence is available regarding the differential expression of IL-10 after RT programs. In MS, IL-10 unequivocally exerts a protective, anti-inflammatory role in the CNS (
      • Samoilova E.B.
      • Horton J.L.
      • Chen Y.
      Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery.
      ). Through the activation of signal transducers and activators of transcription-3 (STAT3), among other transcription factors, it is able to regulate the expression of genes involved in apoptosis, inhibition of cell activation and proliferation, as well as regulate cytokine production (
      • Hu X.
      • Chen J.
      • Wang L.
      • Ivashkiv L.B.
      Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation.
      ;
      • Lai C.F.
      • Ripperger J.
      • Morella K.K.
      • Jurlander J.
      • Hawley T.S.
      • Carson W.E.
      • et al.
      Receptors for interleukin (IL)-10 and IL-6-type cytokines use similar signaling mechanisms for inducing transcription through IL-6 response elements.
      ;
      • Williams L.M.
      • Ricchetti G.
      • Sarma U.
      • Smallie T.
      • Foxwell B.M.J.
      Interleukin-10 suppression of myeloid cell activation - a continuing puzzle.
      ). It also shifts the cytokine expression profile towards the anti-inflammatory side (
      • Moore K.W.
      • de Waal Malefyt R.
      • Coffman R.L.
      • O'Garra A
      Interleukin-10 and the Interleukin-10 receptor.
      ). The decrease in IL-10 reported by
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      could be explained in light of the concurrent decrease in several other pro-inflammatory cytokines observed in the same intervention, suggesting that a reduced expression level of IL-10 may have been a counterregulatory mechanism that serves to balance out the otherwise collective shift towards the anti-inflammatory side. The majority of published literature, however, demonstrates a rise in IL-10 levels following RT (
      • Kazemi F.
      The correlation of resistance exercise-induced myostatin with insulin resistance and plasma cytokines in healthy young men.
      ;
      • Chupel M.U.
      • Direito F.
      • Furtado G.E.
      • Minuzzi L.G.
      • Pedrosa F.M.
      • Colado J.C.
      • et al.
      Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment.
      ).

      4.1.2 BDNF

      Studies show that BDNF levels tend to increase in subjects undergoing RT. BDNF levels appear to be reduced in MS patients compared to healthy controls (
      • Islas-Hernandez A.
      • Aguilar-Talamantes H.S.
      • Bertado-Cortes B.
      • Mejia-delCastillo G de J.
      • Carrera-Pineda R.
      • Cuevas-Garcia C.F.
      • et al.
      BDNF and Tau as biomarkers of severity in multiple sclerosis.
      ), and lower BDNF levels in the sera of MS patients are associated with poorer cognitive performances (
      • Patanella A.K.
      • Zinno M.
      • Quaranta D.
      • Nociti V.
      • Frisullo G.
      • Gainotti G.
      • et al.
      Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients.
      ). The positive effects of BDNF in MS are additionally supported by the improvement in memory and MS-induced dysfunction seen upon vitamin B12-induced rise in BDNF levels (
      • Taherian N.
      • et al.
      Vitamin B12 and estradiol benzoate improve memory retrieval through activation of the hippocampal AKT, BDNF, and CREB proteins in a rat model of multiple sclerosis.
      ).

      4.2 Proinflammatory mediators

      4.2.1 IL-6

      Available evidence indicates the downregulation of IL-6 levels following RT. IL-6 signaling activates STAT3 and MAPK pathways, resulting in the transcription of target genes (
      • Jura J.
      • Węgrzyn P.
      • Korostyński M.
      • Guzik K.
      • Oczko-Wojciechowska M.
      • Jarząb M.
      • et al.
      Identification of interleukin-1 and interleukin-6-responsive genes in human monocyte-derived macrophages using microarrays.
      ). In MS, cells producing IL-6, including T-helper 1 and T-helper 17, appear to contribute to disease progression and inflammation, and PBMCs from MS patients also appear to have higher expression levels of IL-6 compared to healthy controls. Together with IL-17, IL-6 contributes to the alteration in the permeability of BBB seen in MS patients (
      • Kebir H.
      • Kreymborg K.
      • Ifergan I.
      • Dodelet-Devillers A.
      • Cayrol R.
      • Bernard M.
      • et al.
      Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation.
      ). At the same time, it contributes to the differentiation of Th17 and the release of proinflammatory cytokines, including IL-17 (
      • Hirahara K.
      • Ghoreschi K.
      • Laurence A.
      • Yang X.P.
      • Kanno Y.
      • O'Shea J.J
      Signal transduction pathways and transcriptional regulation in Th17 cell differentiation.
      ). Inside the CNS, IL-6 promotes the activation of astrocytes and microglia (
      • Shobeiri P.
      • Seyedmirzaei H.
      • Karimi N.
      • Rashidi F.
      • Teixeira A.L.
      • Brand S.
      • et al.
      IL-6 and TNF-α responses to acute and regular exercise in adult individuals with multiple sclerosis (MS): a systematic review and meta-analysis.
      ). Additionally, higher levels of IL-6 have been correlated with lower cognitive skills and functions in MS patients (
      • Patanella A.K.
      • Zinno M.
      • Quaranta D.
      • Nociti V.
      • Frisullo G.
      • Gainotti G.
      • et al.
      Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients.
      ).

      4.2.2 IL-15

      Literature collectively pointed towards the increase in IL-15 levels in response to RT interventions. IL-15 appears to be pivotal for the maturation, differentiation, and survival of NK cells (
      • Yu J.
      • Freud A.G.
      • Caligiuri M.A.
      Location and cellular stages of natural killer cell development.
      ). IL-15 activates STAT4 and STAT5, and its overexpression appears to be correlated with disease severity in RRMS patients (
      • Zarobkiewicz M.K.
      • Kowalska W.
      • Morawska I.
      • Halczuk P.
      • Rejdak K.
      • Bojarska-Junak A.
      IL-15 is overexpressed in γδ T cells and correlates with disease severity in relapsing-remitting multiple sclerosis.
      ).
      • Broux B.
      • Mizee M.R.
      • Vanheusden M.
      • van der Pol S.
      • van Horssen J.
      • van Wijmeersch B.
      • et al.
      IL-15 amplifies the pathogenic properties of CD4 + CD28 T cells in multiple sclerosis.
      demonstrated that CD4+ CD28- cells, a subset of T-helper (Th) cells, have cytotoxic and proinflammatory properties that are exacerbated upon stimulation with IL-15, ultimately contributing to tissue damage in MS lesions. More studies on RT are needed to ascertain the differential acute versus chronic effects that RT exerts on the immune system provided by bouts versus sustained programs of RT.

      4.2.3 IL-8

      Expression changes in IL-8 levels following RT interventions appear to be negative. The CSF levels of IL-8 are significantly elevated in MS patients compared to healthy controls (
      • Lund B.T.
      • Ashikian N.
      • Ta H.Q.
      • Chakryan Y.
      • Manoukian K.
      • Groshen S.
      • et al.
      Increased CXCL8 (IL-8) expression in multiple sclerosis.
      ;
      • Matejčíková Z.
      • Mareš J.
      • Sládková V.
      • Svrčinová T.
      • Vysloužilová J.
      • Zapletalová J.
      • et al.
      Cerebrospinal fluid and serum levels of interleukin-8 in patients with multiple sclerosis and its correlation with Q-albumin.
      ). IL-8 directs the recruitment of inflammatory cells from the periphery to the CNS; it is produced by a variety of cells, such as microglial and endothelial cells, and acts as a chemotactic agent for monocytes, enhancing their endothelial cell adhesion (
      • Lund B.T.
      • Ashikian N.
      • Ta H.Q.
      • Chakryan Y.
      • Manoukian K.
      • Groshen S.
      • et al.
      Increased CXCL8 (IL-8) expression in multiple sclerosis.
      ).

      4.2.4 TNF-α

      Evidence suggests that post-RT levels of serum TNF-α are decreased. The signaling roles of this cytokine are actually complex in MS, owing to the presence of multiple receptor subtypes, which happen to exert opposing effects (
      • Probert L.
      TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects.
      ;
      • Suvannavejh G.C.
      • Lee H.O.
      • Padilla J.
      • Dal Canto M.C.
      • Barrett T.A.
      • Miller S.D.
      Divergent roles for p55 and p75 tumor necrosis factor receptors in the pathogenesis of MOG35-55-induced experimental autoimmune encephalomyelitis.
      ). While signaling through TNF receptor (TNFR)−1 mediates inflammation and demyelination through the activation of the transcription NF-kB, signaling through TNFR2 appears to promote oligodendrocyte differentiation and remyelination (
      • Arneth B.M.
      Impact of B cells to the pathophysiology of multiple sclerosis.
      ;
      • Madsen P.M.
      • Motti D.
      • Karmally S.
      • Szymkowski D.E.
      • Lambertsen K.L.
      • Bethea J.R.
      • et al.
      Oligodendroglial TNFR2 mediates membrane TNF-Dependent repair in experimental autoimmune encephalomyelitis by promoting oligodendrocyte differentiation and remyelination.
      ). TNFR1 is widely expressed, whereas the expression of TNFR2 is more conservative, primarily restricted to immune cells, endothelial cells, as well as oligodendrocytes and some populations of neurons. Early experimental data involving several clinical trials testing the use of non-selective anti-TNF antibodies in MS patients (encouraged by prior success in EAE model) ironically showed exacerbations in the patients’ disease state. This suggested that TNF plays both a protective role in addition to its neuroinflammatory role in the CNS, and that a distinction is necessary between the downstream effects of each the transmembrane TNF and the soluble TNF, due to their differential affinities to TNFR1 and TNFR2 (
      • Probert L.
      TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects.
      ).

      4.2.5 CCL2

      Serum CCL2 levels are decreased after RT. The CSF levels of CCL2 in active RRMS patients are lower compared to controls, the level of CCL2 increasing with increasing time from relapse (
      • Mahad D.J.
      • Ransohoff R.M.
      The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE).
      ), whereas serum levels remain equivocal across different studies. This prevents a straightforward correlation to be made in light of RT-induced changes in serum CCL2 since no clear serum profile of CCL2 is defined for MS patients, emphasizing the need for precisely establishing a CSF-related change in CCL2 levels following RT. Nevertheless, CCL2 is the main mediator involved in the recruitment of activated inflammatory cells, including lymphocytes and macrophages, from the periphery into the CNS. It also affects these cells’ adhesion, cytokine production, and survival (
      • Gschwandtner M.
      • Derler R.
      • Midwood K.S.
      More than just attractive: how CCL2 influences myeloid cell behavior beyond chemotaxis.
      ), and has been shown to have elevated levels in both acute and chronic MS lesions (
      • McManus C.
      • Berman J.W.
      • Brett F.M.
      • Staunton H.
      • Farrell M.
      • Brosnan C.F.
      MCP-1, MCP-2 and MCP-3 expression in multiple sclerosis lesions: an immunohistochemical and in situ hybridization study.
      ).

      4.2.6 Leptin

      Levels of leptin are reduced in the serum following a combination of RT regime and dietary advice. In RRMS patients, serum leptin levels are higher compared to healthy controls (
      • Frisullo G.
      • Mirabella M.
      • Angelucci F.
      • Caggiula M.
      • Morosetti R.
      • Sancricca C.
      • et al.
      The effect of disease activity on leptin, leptin receptor and suppressor of cytokine signalling-3 expression in relapsing–remitting multiple sclerosis.
      ) Leptin appears to shift the cytokine expression profile towards the proinflammatory side, increasing the risk for developing autoimmune disorders, and circling back to the risk presented by obesity in the development of MS (
      • Versini M.
      • Jeandel P.Y.
      • Rosenthal E.
      • Shoenfeld Y.
      Obesity in autoimmune diseases: not a passive bystander.
      ).

      4.2.7 VEGF

      VEGF levels are reduced in the serum after RT intervention. VEGF serum levels are reportedly higher in all phases of RRMS compared to healthy controls (
      • Amini Harandi A.
      • Siavoshi F.
      • Shirzadeh Barough S.
      • Amini Harandi A.
      • Pakdaman H.
      • Sahraian M.A.
      • et al.
      Vascular endothelial growth factor as a predictive and prognostic biomarker for multiple sclerosis.
      ). Human MS tissue pathology studies show that there is increased angiogenesis in MS lesions, and deeper investigation using MRI scans indicated that this increase in blood vessel formation and CNS perfusion possibly occurred even before lesion development in the early stages of the disease. Furthermore, angiogenesis is stimulated by the hypoxic nature of MS lesions, which entails the impaired mitochondrial function and the increased energy demand in these lesions (
      • Lengfeld J.
      • Cutforth T.
      • Agalliu D.
      The role of angiogenesis in the pathology of multiple sclerosis.
      ). Studies show that VEGF-B inhibits the recovery of astrocytes (
      • Cirac A.
      • Tsaktanis T.
      • Beyer T.
      • Linnerbauer M.
      • Andlauer T.
      • Grummel V.
      • et al.
      The aryl hydrocarbon receptor–dependent TGF-α/VEGF-B ratio correlates with disease subtype and prognosis in multiple Sclerosis.
      ). VEGF-A has also been incriminated in its contribution to CNS inflammation, mediated via MAPK signaling pathway, enhancing vascular permeability and cellular migration. (
      • Azimi G.
      • Ranjbaran F.
      • Arsang-Jang S.
      • Ghafouri-Fard S.
      • Mazdeh M.
      • Sayad A.
      • et al.
      Upregulation of VEGF-A and correlation between VEGF-A and FLT-1 expressions in Iranian multiple sclerosis patients.
      )

      4.2.8 TLR

      Available evidence collectively points towards the inverse correlation between resistance training and TLR expression on the surface of PBMCs. TLRs belong to a family of pattern recognition receptors (PPRs) and normally respond to molecules known as danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). In MS, these receptors are responsible for mediating many of the downstream pathogenic effects of inflammatory cells such as Th1 and Th17 in the disease, as well as downplaying the modulatory effects of T-regulatory (Treg) cells. TLR cell-surface expression is additionally increased in MS patients compared to healthy individuals (
      • Jafarzadeh A.
      • Nemati M.
      • Khorramdelazad H.
      • Mirshafiey A.
      The Toll-like Receptor 2 (TLR2)-related immunopathological responses in the multiple sclerosis and experimental autoimmune encephalomyelitis.
      ).

      4.3 KYN/TRP ratio

      Finally, a transient elevation was reported in KYN/TRP ratio following RT. The conversion of TRP to KYN is mediated by an enzyme called indoleamine-2,3-dioxygenase-1, the activation of which is triggered by inflammatory cytokines, such as IL-6. KYN metabolites have both neurotoxic and neuroprotective properties; an elevation in the KYN/TRP ratio has therefore unsurprisingly been consistently implicated in the context of many inflammatory and neurodegenerative diseases (
      • Schwarcz R.
      • Bruno J.P.
      • Muchowski P.J.
      • Wu H.Q.
      Kynurenines in the mammalian brain: when physiology meets pathology.
      ). However, short-term rises in KYN/TRP ratio are associated with a number of neuroprotective and beneficial effects, and must be distinguished from the neurotoxicity-inducing chronic rise in KYN/TRP ratio. An increase in KYN/TRP ratio suppresses T-cell mediated response in MS (
      • Mancuso R.
      • Hernis A.
      • Agostini S.
      • Rovaris M.
      • Caputo D.
      • Fuchs D.
      • et al.
      Indoleamine 2,3 dioxygenase (IDO) expression and activity in relapsing- remitting multiple sclerosis.
      ), and KYN is able to inhibit the inflammatory response in EAE models (
      • Quintana F.J.
      • Murugaiyan G.
      • Farez M.F.
      • Mitsdoerffer M.
      • Tukpah A.M.
      • Burns E.J.
      • et al.
      An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis.
      ). In contrast, a chronic elevation in this ratio causes increased production of the neurotoxic metabolite of KYN, quinolinic acid (
      • Lim C.K.
      • Bilgin A.
      • Lovejoy D.B.
      • Tan V.
      • Bustamante S.
      • Taylor B v.
      • et al.
      Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression.
      )
      The aforementioned cytokines, along with their roles in MS pathology and the effects brought upon by RT, are summarized in Table 3.
      Table 3RT-associated differentially-expressed inflammatory key players in MS pathology. RT: resistance training; MS: multiple sclerosis; IL: interleukin; TNF: tumor necrosis factor; TNFR: tumor necrosis factor receptor; BDNF: brain-derived neurotrophic factor; CCL: C C chemokine ligand; VEGF: vascular endothelial growth factor; TLR: toll-like receptor; KYN/TRP: kynurenine/tryptophan.
      Inflammatory mediatorRole in MS pathologyEffect of RT
      IL-10Anti-inflammatory; protective (
      • Samoilova E.B.
      • Horton J.L.
      • Chen Y.
      Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery.
      )
      Reduced (counterregulatory mechanism?) (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )

      Increase (
      • Kapilevich L.V.
      • Zakharova A.N.
      • Kabachkova A.V.
      • Kironenko T.A.
      • Orlov S.N
      Dynamic and static exercises differentially affect plasma cytokine content in elite endurance- and strength-trained athletes and untrained volunteers.
      ;
      • Chupel M.U.
      • Direito F.
      • Furtado G.E.
      • Minuzzi L.G.
      • Pedrosa F.M.
      • Colado J.C.
      • et al.
      Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment.
      )
      IL-6Proinflammatory; disease progression (
      • Patanella A.K.
      • Zinno M.
      • Quaranta D.
      • Nociti V.
      • Frisullo G.
      • Gainotti G.
      • et al.
      Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients.
      )
      Decreased (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )
      IL-15Proinflammatory (
      • Zarobkiewicz M.K.
      • Kowalska W.
      • Morawska I.
      • Halczuk P.
      • Rejdak K.
      • Bojarska-Junak A.
      IL-15 is overexpressed in γδ T cells and correlates with disease severity in relapsing-remitting multiple sclerosis.
      )
      Increased (differential effects of acute VS chronic RT?) (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )
      BDNFNeuroprotective (
      • Islas-Hernandez A.
      • Aguilar-Talamantes H.S.
      • Bertado-Cortes B.
      • Mejia-delCastillo G de J.
      • Carrera-Pineda R.
      • Cuevas-Garcia C.F.
      • et al.
      BDNF and Tau as biomarkers of severity in multiple sclerosis.
      )
      Increased (
      • Church D.D.
      • Hoffman J.R.
      • Mangine G.T.
      • Jajtner A.R.
      • Townsend J.R.
      • Beyer K.S.
      • et al.
      Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise.
      )
      IL-8Proinflammatory; enhances endothelial cell adhesion (
      • Lund B.T.
      • Ashikian N.
      • Ta H.Q.
      • Chakryan Y.
      • Manoukian K.
      • Groshen S.
      • et al.
      Increased CXCL8 (IL-8) expression in multiple sclerosis.
      )
      Decreased (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )
      TNF-αTNFR1 signaling – proinflammatory (
      • Gimenez M.A.T.
      • Sim J.E.
      • Russell J.H.
      TNFR1-dependent VCAM-1 expression by astrocytes exposes the CNS to destructive inflammation.
      )

      TNFR2 signaling – remyelination (
      • Arnett H.A.
      • Mason J.
      • Marino M.
      • Suzuki K.
      • Matsushima G.K.
      • Ting J.P.Y.
      TNFα promotes proliferation of oligodendrocyte progenitors and remyelination.
      )
      Decreased (
      • Bazgir B.
      • Salesi M.
      • Koushki M.
      • Amirghofran Z.
      Effects of eccentric and concentric emphasized resistance exercise on il-15 serum levels and its relation to inflammatory markers in athletes and non-athletes.
      ;
      • Chupel M.U.
      • Direito F.
      • Furtado G.E.
      • Minuzzi L.G.
      • Pedrosa F.M.
      • Colado J.C.
      • et al.
      Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment.
      ;
      • Greiwe J.S.
      • Cheng B.
      • Rubin D.C.
      • Yarasheski K.E.
      • Semenkovich C.F
      Resistance exercise decreases skeletal muscle tumor necrosis factor α in frail elderly humans.
      )
      CCL-2Proinflammatory (
      • Glabinski A.R.
      • Tani M.
      • Tuohy V.K.
      • Tuthill R.J.
      • Ransohoff R.M.
      Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis.
      )
      Decreased (
      • Lopes L.M.P.
      • Oliveira E.C.D.
      • Becker L.K.
      • Costa G.D.P.
      • Pinto K.M.D.C.
      • Talvani A.
      • et al.
      Resistance training associated with dietetic advice reduces inflammatory biomarkers in the elderly.
      )
      LeptinShifts cytokine expression profile to the proinflammatory side (
      • Frisullo G.
      • Mirabella M.
      • Angelucci F.
      • Caggiula M.
      • Morosetti R.
      • Sancricca C.
      • et al.
      The effect of disease activity on leptin, leptin receptor and suppressor of cytokine signalling-3 expression in relapsing–remitting multiple sclerosis.
      )
      Decreased (in combination with dietary advice) (
      • Lopes L.M.P.
      • Oliveira E.C.D.
      • Becker L.K.
      • Costa G.D.P.
      • Pinto K.M.D.C.
      • Talvani A.
      • et al.
      Resistance training associated with dietetic advice reduces inflammatory biomarkers in the elderly.
      )
      VEGFDecreases astrocyte recovery; proinflammatory (
      • Azimi G.
      • Ranjbaran F.
      • Arsang-Jang S.
      • Ghafouri-Fard S.
      • Mazdeh M.
      • Sayad A.
      • et al.
      Upregulation of VEGF-A and correlation between VEGF-A and FLT-1 expressions in Iranian multiple sclerosis patients.
      )
      Decreased (
      • Despeghel M.
      • Reichel T.
      • Zander J.
      • Krüger K.
      • Weyh C.
      Effects of a 6 week low-dose combined resistance and endurance training on t cells and systemic inflammation in the elderly.
      )
      TLRPromotes downstream inflammatory responses (
      • Jafarzadeh A.
      • Nemati M.
      • Khorramdelazad H.
      • Mirshafiey A.
      The Toll-like Receptor 2 (TLR2)-related immunopathological responses in the multiple sclerosis and experimental autoimmune encephalomyelitis.
      )
      Decreased (
      • Mcfarlin B.K.
      • Flynn M.G.
      • Campbell W.W.
      • Stewart L.K.
      • Timmerman K.L
      TLR4 is lower in resistance-trained older women and related to inflammatory cytokines.
      ;
      • Saqqezi S.
      • et al.
      Combined training improves the expression profile of inflammation-associated antimicrobial peptides, MicroRNAs, and TLR-4 in patients with multiple sclerosis.
      )
      KYN/TRP ratioAcute elevation – decreased T-cell responses; anti-inflammatory

      Chronic elevation – neurotoxic

      (
      • Vancassel S.
      • Capuron L.
      • Castanon N.
      Brain kynurenine and BH4 pathways: relevance to the pathophysiology and treatment of inflammation-driven depressive symptoms.
      ;
      • Mándi Y.
      • Vécsei L.
      The kynurenine system and immunoregulation.
      ;
      • Lim C.K.
      • Bilgin A.
      • Lovejoy D.B.
      • Tan V.
      • Bustamante S.
      • Taylor B v.
      • et al.
      Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression.
      ;
      • Schwarcz R.
      • Bruno J.P.
      • Muchowski P.J.
      • Wu H.Q.
      Kynurenines in the mammalian brain: when physiology meets pathology.
      )
      Transient increase (
      • Joisten N.
      • et al.
      Exercise and the Kynurenine pathway: current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training.
      )
      After seeding the understanding that one of the mechanisms by which RT may contribute to an overall enhanced well-being of MS patients may be through altering certain key players the immune system, a review of already published evidence establishing this correlation is needed in order to further fortify this notion. As such, literature investigating the immunoregulatory role of RT in MS patients will be reviewed in the following section.

      5. How resistance training shapes the immune systems of multiple sclerosis patients

      A study conducted on 30 female RRMS patients with EDSS between 2 and 6 showed that an 8-week duration of progressive Pilates (considered as a light form of resistance training) was associated with a significant increase in BDNF (p = 0.03). The training session included 2 rounds of warmup exercises, followed by 30–40 min of the main exercises (hundred, roll-up, roll-down, single leg circle movements); progression was achieved by gradually increasing the number of reps and decreasing rest time (
      • Eftekhari E
      • et al.
      Interleukin-10 and brain-derived neurotrophic factor responses to the Mat Pilates training in women with multiple sclerosis.
      ).
      In 2020, a case report was published on a secondary progressive MS (SPMS) patient, with EDSS 4.5, who showed a decrease in high-molecular weight adiponectin, the main mediator of inflammation attributed to adipokines, following a 6-month RT and aerobic training protocol. The training program consisted of resistance machine exercises (leg press, leg extension, leg curl, vertical traction, row pull, abdominal crunches), followed by 10 min on a stationary bike at 65% effort (
      • Grazioli E.
      • Nigro E.
      • Cerulli C.
      • Borriello G.
      • Mancini A.
      • Tranchita E.
      • et al.
      Case report: concurrent resistance and aerobic training regulate adiponectin expression and disease severity in multiple sclerosis: a case study.
      ).
      Additionally, a 12-week randomized controlled trial investigated the effect of a combined exercise program consisting of RT and endurance exercise on innate markers of inflammation in 38 MS patients with EDSS <6. This progressive training program included cycling and treadmill walking/running, followed by RT which included unilateral lower-limb movements (leg press, leg curl, leg extension) and vertical traction, arm curl, and chest press. It showed that the levels of matrix metalloproteinase-2 (MMP2) and TNF-α were significantly reduced (p = 0.04 and p = 0.029, respectively) upon stimulation of TLRs with lipopolysaccharide (LPS) or interferon-gamma (IFN-γ) after the intervention compared to baseline (
      • Deckx N.
      • Wens I.
      • Nuyts A.H.
      • Hens N.
      • de Winter B.Y.
      • Koppen G.
      • et al.
      12 weeks of combined endurance and resistance training reduces innate markers of inflammation in a randomized controlled clinical trial in patients with multiple sclerosis.
      ).
      Finally, another 2021 study showed that RT combined with aerobic training significantly reduced the levels of some inflammatory markers and microRNAs (miRNAs). This program was carried out for 8 weeks on 12 RRMS patients aging from 20 to 40 years with EDSS between 1 and 4. Aerobic training was carried out on a treadmill or a stationary bike, and RT was progressive loads from 50%−70% in knee flexion and extension exercises. Increases in TLR4, miR-326, and miR-155 were significantly lower than controls (p = 0.001 for all), whereas miR-326 significantly decreased compared to controls (p = 0.001) (
      • Saqqezi S.
      • et al.
      Combined training improves the expression profile of inflammation-associated antimicrobial peptides, MicroRNAs, and TLR-4 in patients with multiple sclerosis.
      ).
      The afore-discussed studies, along with their findings are summarized in Table 4. These changes are also summarized in Fig. 1, and the overall relationship between RT, downstream molecular effects, and MS patients’ physical and mental outcomes, is summarized in Fig. 2.
      Table 4Summary of the different RT-based interventions on signaling molecules in MS patients. RT: resistance training; EDSS: estimated disability status score; BDNF: brain-derived neurotrophic factor; SPMS: secondary progressive multiple sclerosis; PRT: progressive resistance training; TNF: tumor necrosis factor; MMP: matrix-metalloproteinase; TLR: toll-like receptor; miR: micro-RNA.
      StudyInterventionEDSSDurationOutcome (p value)
      (
      • Eftekhari E
      • et al.
      Interleukin-10 and brain-derived neurotrophic factor responses to the Mat Pilates training in women with multiple sclerosis.
      )
      Progressive Pilates program: warmup exercises followed by 30–40 min of hundred, roll up, roll down, and single-leg circular movements.2–68 weeksIncreased BDNF (p = 0.03)
      (
      • Grazioli E.
      • Nigro E.
      • Cerulli C.
      • Borriello G.
      • Mancini A.
      • Tranchita E.
      • et al.
      Case report: concurrent resistance and aerobic training regulate adiponectin expression and disease severity in multiple sclerosis: a case study.
      ) (case report)
      RT + aerobic training (stationary bike)

      RT: leg press, leg extension, leg curl, vertical traction, row pull, abdominal crunches.
      One SPMS patient with EDSS 4.54 monthsDecreased adiponectin
      (
      • Deckx N.
      • Wens I.
      • Nuyts A.H.
      • Hens N.
      • de Winter B.Y.
      • Koppen G.
      • et al.
      12 weeks of combined endurance and resistance training reduces innate markers of inflammation in a randomized controlled clinical trial in patients with multiple sclerosis.
      )
      RT + endurance training (cycling/treadmill walk/run)

      RT: unilateral lower limb (leg press, leg curl, leg extension) + vertical traction, arm curl, chest press.
      <612 weeksDecreased TNF-α (p = 0.029)

      Decreased MMP-9 (p = 0.04)
      (
      • Saqqezi S.
      • et al.
      Combined training improves the expression profile of inflammation-associated antimicrobial peptides, MicroRNAs, and TLR-4 in patients with multiple sclerosis.
      )
      PRT + aerobic training (treadmill walk/run or stationary bike)

      RT: knee flexion and knee extension
      1–48 weeksLower increase in TLR4, miR-326, miR-155 (p = 0.001)

      Decrease in miR-23b (p = 0.001)
      Fig 1
      Fig. 1The effects of RT on immune components of MS patients. RT: resistance training; MS: multiple sclerosis; Th: T-helper cells; Treg: T-regulatory cells; BDNF: brain-derived neurotrophic factor; TLR: toll-like receptor; miR: micro-RNA; MMP: matrix metalloproteinase; TNF: tumor necrosis factor.
      Fig 2
      Fig. 2One of the mechanisms by which RT may improve MS patients' quality of life may be through altering key immune system components. RT: resistance training; MS: multiple sclerosis; Th: T-helper cells; Treg: T-regulatory cells; BDNF: brain-derived neurotrophic factor; TLR: toll-like receptor; miR: micro-RNA; EDSS: estimated disability status score.

      6. Conclusion

      As a complex and multifactorial disease, MS presents its own set of challenges when it comes to its treatment. Of particular importance among the barriers to successful MS management is the inconsistency in treatment responses across patients of seemingly similar characteristics. Aside from the emerging role of epigenetics in the development, progression, and treatment responses in this disease, additional interventions are increasingly required to improve patient functionality and QoL. Among the many non-pharmacological interventions used for improving patient disability is the use of exercise, of particular interest in this review being RT. RT is regarded as the single most effective treatment modality for increasing muscle mass in humans, and this gain in strength has been proven across literature to be ultimately beneficial to MS patients in terms of ameliorating fatigue, increasing functionality and mobility, and on the molecular level, affecting key players of the immune system of patients in a way that contributes to their overall well-being. Key players affected as a result of RT have been reviewed, and they include IL-10, IL-6, IL-15, BDNF, CCL2, among others. These mediators have been shown by literature to be differentially expressed in resistance-trained versus untrained individuals. Moreover, the roles of these molecules in MS pathology have also been listed and summarized. Finally, published evidence has been demonstrated that show how RT carried out in MS subjects affects certain components in the immune system, including all the aforementioned targets, as well as other targets that have not yet been investigated with regards to RT in general, such as MMP-2, miR-23b, miR-155, and miR-326. This suggests that as literary evidence advances, RT may well be proven exceedingly beneficial in MS patients (possibly more than in healthy individuals), as a non-pharmacological disease-modifying strategy in attenuating hyperactive immune responses and mediating neuroprotection in the CNS, ultimately contributing to the increased QoL of MS patients (Fig. 2).

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      The authors declare no conflict of interests.

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