Exercise-induced exerkines in multiple sclerosis: Emphasizing the pivotal role of myokines

Multiple sclerosis (MS) is the most common chronic inflammatory and neurodegenerative disease of the central nervous system in young adults. While existing immunomodulatory therapies reduce relapse rates, they are less effective against the progressive neurodegeneration associated with the disease. This unmet clinical need has prompted interest in complementary non-pharmacological strategies, particularly exercise, which offers systemic anti-inflammatory and neuroprotective benefits. Exercise triggers the release of a diverse array of signaling molecules collectively known as exerkines. Among these, myokines, such as interleukin‑6 (IL‑6), brain‑derived neurotrophic factor (BDNF), and irisin, are secreted by contracting skeletal muscle, functioning through endocrine, paracrine, and autocrine mechanisms to modulate immune responses, reduce inflammation, and promote neural repair. To date, there are limited studies that comprehensively review exercise-induced exerkines and myokines in the context of MS, leaving a critical gap in translating these molecular insights into clinical practice. In this review, we critically examine the emerging role of exercise-induced exerkines in MS, with a special emphasis on myokines. We discuss how these bioactive factors contribute to the establishment of a muscle-brain axis capable of influencing disease processes, including neuroinflammation, remyelination, and neurodegeneration. Drawing upon evidence from neurodegenerative disease models and clinical studies, we highlight how exercise modalities may be harnessed to optimize myokine release and, in turn, enhance neuroprotection and repair in MS patients. This synthesis underscores the potential of exercise as an adjunct therapy in MS management and outlines future research directions aimed at integrating exercise-induced myokine modulation into comprehensive treatment strategies.