Exercise-Associated Fatigue Modulation in Multiple Sclerosis: A Meta-Analysis of MFIS Outcomes Within a Proposed Extracellular Vesicle Framework

Abstract

Context: Fatigue in multiple sclerosis (MS) affects three domains: physical, mental, and social. Exercise holds therapeutic promise because of its potential benefits for health and well-being. However, the biological mechanisms underlying these effects remain poorly understood, particularly with respect to extracellular vesicles (EVs). Moreover, little is known about the interaction between exercise and EVs, or the potential role of EVs in mediating exercise-related health benefits. This systematic review and meta-analysis synthesizes current evidence on how various types of exercise modulate fatigue in MS, assessed using the Modified Fatigue Impact Scale (MFIS), with a focus on EV-driven neurofunctional adaptations. Evidence Acquisition: This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eleven randomized controlled trials (RCTs) involving 665 participants were included. Subgroup analyses and random-effects modeling were performed using Stata 15 to assess domain-specific effects and modality-based differences. Results: Exercise interventions significantly reduced fatigue across all MFIS domains. The largest effects were observed for physical fatigue (pooled effect size [ES]: −4.486; 95% confidence interval [CI]: −5.502 to −3.470), followed by cognitive fatigue (−2.792; 95% CI: −3.810 to −1.775) and psychosocial fatigue (−0.938; 95% CI: −1.226 to −0.650). Aquatic and coordination-based exercises showed the most consistent and substantial improvements. Discussion: This meta-analysis highlights the therapeutic role of exercise in alleviating MS-related fatigue, with modality-specific benefits suggesting distinct underlying biological mechanisms. Integrating MFIS outcomes with emerging EV literature may provide a hypothesis-generating framework for future mechanism-oriented rehabilitation research in multiple sclerosis.