Summary: New neuroimmunology research identifies a cellular mechanism that helps explain why exercise improves neurological symptoms in multiple sclerosis (MS). The study shows that irisin, a hormone released by muscles during physical activity, has a direct and potent neuroprotective effect in the central nervous system, protecting neurons from inflammation-driven degeneration.
Using an established mouse model of MS, investigators demonstrated that irisin reduces neuronal loss, preserves synapses, and restores a protective gene program in affected neurons. These findings point to irisin as a promising therapeutic target for progressive MS, where current anti-inflammatory treatments often fail to prevent long-term neurodegeneration.
Key Facts
- The myelin assault: Multiple sclerosis is an autoimmune, neurodegenerative disease in which the immune system damages the myelin sheaths that insulate neurons in the brain and spinal cord.
- Irisin, the exercise hormone: Produced by muscle during aerobic activity, irisin markedly reduced clinical symptoms and neuron loss in experimental MS models.
- Genetic validation: Removing the gene for irisin abolished exercise’s neuroprotective benefits in mice, while restoring irisin rescued neurons and improved outcomes.
- Three-compartment protection: Irisin prevented neuronal loss in the spinal cord, hippocampus, and retina, limited synaptic degeneration, and reinstated neuroprotective gene expression.
- Direct neuronal action: Rather than suppressing peripheral immune responses, irisin appears to act directly on neurons to preserve structure and function during inflammatory attack.
- Complex biology: Although irisin is a clear drug-development target, exercise’s benefits in MS are multifactorial and likely involve many interacting molecules and systemic effects.
Study overview
Researchers from Mass General Brigham and the University Medical Center Hamburg-Eppendorf (UKE) analyzed the role of irisin in experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of multiple sclerosis. They found that voluntary aerobic exercise protected mice from inflammation-induced neurodegeneration, but that protection depended on the presence of the irisin precursor Fndc5. Mice lacking Fndc5/irisin did not receive the neuroprotective benefits of exercise, while peripheral administration of irisin restored protection and reduced clinical disease severity.
Mechanistically, peripheral irisin raised circulating irisin levels and reduced neuronal loss and clinical signs in EAE mice. Importantly, peripheral irisin did not significantly change peripheral or central immune profiles in this model. Instead, the hormone induced a neuroprotective transcriptional program in spinal cord neurons, preserved synaptic structures, and supported mitochondrial function—consistent with a direct action on motor neurons.
Implications
Current MS therapies largely target immune inflammation but have limited success preventing progressive neuronal decline. By acting directly on neurons rather than suppressing peripheral immunity, irisin represents a new strategy focused on neuroprotection. These findings support further research into irisin-based therapies for progressive forms of MS and underline the importance of exercise-induced systemic signals in brain health.
Author perspectives
Christiane D. Wrann, DVM, PhD, leader of the Program in Neuroprotection in Exercise at Mass General Brigham Neuroscience Institute, said the study strengthens the case for developing irisin as a therapeutic candidate, particularly for progressive MS. First author Sina C. Rosenkranz, MD, emphasized that an exercise-induced molecule can directly protect neurons in a model of MS, revealing a new mechanism by which physical activity can influence neurodegeneration. Co-senior author Ruxandra F. Sîrbulescu, PhD, noted that the team did not observe a direct suppression of peripheral immune responses by irisin, highlighting its neuron-centered mode of action.
Frequently asked questions
A: During exercise, active muscle secretes irisin into the bloodstream. This study shows that irisin reaches the central nervous system and acts directly on neurons—particularly motor neurons—preserving synapses and cellular function so neurons resist inflammation-driven damage.
A: Existing therapies are effective at lowering immune-driven inflammation but are less able to stop the progressive loss of neurons that causes long-term disability. Irisin offers a complementary strategy by protecting neurons directly, which could slow or prevent neurodegeneration even when inflammation occurs.
A: No. The mouse study demonstrates that irisin is required for exercise’s neuroprotective effect in this model, but MS is a complex, multifactorial disease. Exercise produces many beneficial changes beyond irisin release, and further research is necessary to translate these findings into safe, effective human therapies.
Editorial notes
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional contextual information was added by editorial staff.
About this multiple sclerosis research news
Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image credit: Neuroscience News
Original research: Open access. “The exercise hormone irisin has neuroprotective effects in a mouse model of multiple sclerosis” by Sina C. Rosenkranz et al., published in Nature Metabolism. DOI: 10.1038/s42255-026-01527-7
Abstract (condensed)
Aerobic exercise modifies disease course in multiple sclerosis and can improve progressive neurological symptoms. This study demonstrates that the exercise-induced hormone irisin mediates key neuroprotective effects in the EAE mouse model of MS. Voluntary running protected against inflammation-induced neurodegeneration, but this protection required Fndc5/irisin. Peripheral irisin administration increased plasma irisin, reduced clinical symptoms, and limited neuronal loss without altering overt peripheral or central immune responses. Instead, irisin activated a neuroprotective gene program, preserved synapses and mitochondrial activity, and likely acted through direct binding to motor neurons. Overall, irisin induction by exercise confers direct neuronal protection in an inflammation-driven neurodegenerative condition and represents an attractive candidate for therapeutic development in MS.
Authorship and disclosures
Key contributors include Christiane D. Wrann, Sina C. Rosenkranz, Ruxandra F. Sîrbulescu, Joana F. da Rocha, Luis Moreira, and many co-authors listed in the original paper. Relevant disclosures: Wrann holds a patent related to irisin (WO2015051007A1), is an academic co-founder and consultant for Aevum Therapeutics, and has financial interests in that company. Wrann also received honoraria from Novartis; these interests have been reviewed and managed by Massachusetts General Hospital and Mass General Brigham. Other authors reported unrelated honoraria or consulting fees disclosed in the paper.
Funding
Funding sources include several National Institutes of Health grants, the Cure Alzheimer’s Fund, awards from the McCance Center for Brain Health and other foundations, German research fellowships and grants, the National MS Society, and additional institutional and philanthropic support as detailed in the published article.