Exercise Hormone Irisin Reveals Neuroprotective Effects in Multiple Sclerosis

By VirentaNews Staff — May 21, 2026

Emerging research provides a mechanistic explanation for the long-observed benefits of exercise in multiple sclerosis (MS), identifying the myokine irisin as a critical neuroprotective agent. In a study published in Nature Metabolism, scientists from Mass General Brigham and the University Medical Center Hamburg-Eppendorf (UKE) demonstrate that irisin, a hormone released by skeletal muscles during physical activity, crosses the blood-brain barrier and mitigates neuroinflammation and demyelination in a mouse model of MS. These findings not only validate clinical observations that regular exercise improves neurological function in MS patients but also open the door to potential therapeutic strategies that mimic or enhance irisin’s action to slow disease progression.

Irisin Reduces Demyelination and Inflammation in Preclinical Models

Using the experimental autoimmune encephalomyelitis (EAE) mouse model, which replicates key features of human MS, researchers measured irisin levels before and after exercise regimens and during disease progression. Mice that underwent voluntary wheel running showed significantly higher serum and cerebrospinal fluid levels of irisin and a 40% reduction in brain lesions compared to sedentary controls. Histopathological analysis revealed preserved myelin integrity and reduced infiltration of pro-inflammatory T cells in the central nervous system. Further, when irisin was administered directly to sedentary EAE mice, it replicated the protective effects of exercise, decreasing microglial activation by 35% and suppressing levels of IL-6 and TNF-alpha, two key cytokines involved in neuroinflammation. These results, published in Nature Metabolism, establish a direct causal link between irisin and neuroprotection in MS-like conditions.

Key Players: Researchers and Institutions Driving Discovery

The study was co-led by Dr. Francesca Branca at Mass General Brigham and Dr. Jorge Plutzky at Brigham and Women’s Hospital, in collaboration with Dr. Heinz Reichmann from UKE’s Department of Neurology. The interdisciplinary team combined expertise in immunometabolism, neurology, and exercise physiology to explore how systemic changes from physical activity translate into central nervous system benefits. Mass General Brigham contributed advanced imaging and cytokine profiling capabilities, while UKE provided specialized models of neuroinflammatory disease and molecular analysis of neural tissue. Their joint effort underscores a growing trend in translational neuroscience: treating the body as an integrated system rather than isolating neurological conditions from metabolic and muscular function. The collaboration has since secured additional funding from the National Multiple Sclerosis Society to explore irisin-based therapeutics in human trials.

Trade-Offs: Balancing Therapeutic Potential and Biological Complexity

While the discovery of irisin’s neuroprotective role is promising, translating it into clinical applications presents challenges. On one hand, harnessing irisin could lead to injectable or gene-based therapies for patients unable to exercise due to advanced disability, potentially slowing cognitive and motor decline. On the other hand, irisin operates within a complex network of exercise-induced molecules, including BDNF and FNDC5, making it difficult to isolate its effects fully. Moreover, high-dose exogenous irisin could disrupt metabolic homeostasis, as the hormone also influences glucose uptake and bone remodeling. There is also concern that pharmaceutical development might overshadow non-pharmacological interventions, despite exercise being a low-cost, accessible, and holistic strategy with broad health benefits beyond MS. Thus, the optimal path may involve combination approaches that enhance endogenous irisin release through tailored physical regimens alongside targeted biologic support.

Timing: Why This Discovery Is Emerging Now

This breakthrough arrives amid growing recognition of the role of exercise in modifying disease trajectories in neurodegenerative conditions, from MS to Parkinson’s. Advances in proteomics and blood-brain barrier permeability testing have only recently enabled researchers to track how peripheral hormones influence neural tissue. Additionally, the development of sensitive assays for irisin—once considered difficult to measure accurately—has clarified its physiological relevance. The convergence of improved biomolecular tools, robust animal models, and increased focus on lifestyle medicine has created a fertile environment for discoveries like this. With over 2.8 million people living with MS worldwide, and no cure available, the timing of this research is critical for informing both patient care guidelines and next-generation therapeutics.

Where We Go From Here

In the next 6 to 12 months, researchers anticipate launching a phase I clinical trial to assess the safety and bioavailability of recombinant irisin in MS patients. Parallel efforts will focus on identifying exercise protocols that maximize irisin release, particularly in individuals with moderate to severe disability. A third avenue involves developing small molecules or gene therapies that upregulate FNDC5, the precursor protein to irisin, offering a longer-acting alternative to injections. These scenarios—pharmacological intervention, optimized physical therapy, and genetic modulation—represent complementary paths toward integrating irisin science into clinical neurology. If successful, they could redefine MS management by shifting emphasis from solely suppressing immunity to actively promoting neural resilience.

Bottom line — The identification of irisin as a mediator of exercise-induced neuroprotection in MS marks a pivotal advance in understanding how lifestyle interventions alter disease biology, offering both mechanistic insight and tangible pathways for next-generation therapies.

Source: MedicalXpress