Summary: A new neuroimmunology study identifies how exercise improves neurological outcomes in multiple sclerosis (MS). The study shows that irisin — a hormone released by muscle during physical activity — acts directly within the central nervous system to protect neurons from inflammation-driven degeneration, reduce synaptic loss, and reactivate protective gene programs. These findings point to irisin as a promising therapeutic target for progressive MS.
Using an established mouse model of MS, investigators demonstrated that irisin protects neurons from inflammatory damage, limits synapse loss, and improves clinical measures of disease. When irisin was genetically removed, the neuroprotective benefits of exercise disappeared; restoring irisin levels rescued neurons and improved outcomes, supporting a causal role for this exercise-induced hormone.
Key Facts
- The myelin attack: Multiple sclerosis is a chronic, autoimmune neurodegenerative disease in which the immune system damages myelin sheaths that insulate neurons in the brain and spinal cord.
- Irisin, an exercise hormone: Irisin is produced by muscle during aerobic activity and, in this study, markedly reduced clinical signs and neuronal loss in an experimental MS model.
- Genetic knockout reverses benefit: Deleting the gene for irisin eliminated the neuroprotective effects of exercise; reintroducing irisin restored protection and improved clinical status.
- Widespread central protection: Irisin lessened neuronal loss in three central nervous system regions — spinal cord, hippocampus, and retina — preserved synapses, and reinstated a neuroprotective transcriptional program.
- Direct neuronal effect: The hormone did not act by broadly suppressing peripheral immune responses. Instead, evidence indicates irisin directly stabilizes and protects neurons from inflammation-driven decay.
- Complex biology: While irisin is a clear molecular mediator of exercise’s benefits, the authors stress that exercise likely invokes many complementary factors and pathways that together affect MS outcomes.
Source: Mass General
New findings clarify how exercise can help people with multiple sclerosis
Researchers from Mass General Brigham and the University Medical Center Hamburg‑Eppendorf (UKE) examined how levels of irisin influence disease in a mouse model of MS. They found that voluntary aerobic exercise raised irisin levels and protected against inflammation-induced neurodegeneration. Peripheral administration of irisin increased plasma hormone levels and reduced both clinical severity and neuronal loss.
In the experimental autoimmune encephalomyelitis (EAE) model, removing the gene that encodes irisin abolished the protective effect of exercise. Conversely, restoring irisin levels preserved neuronal integrity and improved behavioral outcomes. The authors report that peripheral irisin delivery does not alter the overall peripheral or central immune response but instead triggers a neuron-specific protective gene program, maintains synaptic and mitochondrial function, and appears to act through direct interactions with motor neurons.
These observations suggest that irisin released during exercise confers direct neuroprotection in an inflammation-driven neurodegenerative setting, supporting the idea that targeting this pathway could be beneficial for progressive forms of MS where current anti-inflammatory treatments offer limited protection against neurodegeneration.
“We are optimistic that our study will support further development of irisin as a potential therapeutic, particularly for progressive MS,” said Christiane D. Wrann, DVM, PhD, senior and corresponding author and leader of the Program in Neuroprotection in Exercise at Mass General Brigham Neuroscience Institute and the McCance Center for Brain Health at Massachusetts General Hospital. The team notes these findings also reinforce irisin’s broader neuroprotective potential in multiple neurodegenerative contexts.
Previous work from the same group showed irisin can improve cognitive function and reduce neuroinflammation in mouse models of Alzheimer’s disease. The current study extends those results to an autoimmune-driven model of MS and highlights irisin’s consistent neuron-focused protective actions.
Lead author Sina C. Rosenkranz, MD, emphasized the novelty: an exercise-induced molecule can directly protect neurons in an MS model, revealing a new mechanism by which exercise influences neurodegeneration. Co-senior author Ruxandra F. Sîrbulescu, PhD, added that the data point to direct neuronal stabilization rather than broad immune suppression as the primary mode of action.
The authors caution that additional research is needed to fully delineate how irisin interacts with neuronal receptors and signaling networks, and to determine how this knowledge can be translated into safe, effective therapies for people with MS. They also stress that exercise’s clinical benefits are likely multifactorial and not solely due to irisin.
Authorship: The study’s authors include Christiane D. Wrann, Sina C. Rosenkranz, Ruxandra F. Sîrbulescu, Joana F. da Rocha, Luis Moreira, Pius Schlachter, Jasmina Bier, Kaela Healy, Daniela Neves Silva, Mohamed Ariff Iqbal, Marjan Gharagozloo, Yueyue Xiong, Matthew A. Murphy, Helena C. Lichtenfeld, Lukas Raich, Michaela Schweizer, Asude Ertaş, Marcel S. Woo, Vanessa Vieira, Samuel E. Honeycutt, James P. White, Gregory A. Wyant, Manuel A. Friese, and Peter A. Calabresi, among others.
Disclosures: Christiane Wrann holds a patent related to irisin (WO2015051007A1), is an academic co‑founder and consultant for Aevum Therapeutics, and has a financial interest in that company. Wrann received honoraria from Novartis outside the scope of this work. Interests were reviewed and managed by Massachusetts General Hospital and Mass General Brigham. Rosenkranz has received speaker honoraria from Merck, Roche, and Sanofi. Calabresi has consulted for Lilly and Novartis and is principal investigator on a grant from Genentech. Marcel S. Woo received honoraria from Lilly and Eisai. These disclosures were reported by the authors.
Funding: Research support included grants from the National Institutes of Health, the Cure Alzheimer’s Fund, McCance Center SPARC Award, the Hassenfeld Clinical Scholar Award, Claflin Distinguished Scholar Award, Boehringer Ingelheim Fonds travel grant, the Advanced Clinician–Scientist Fellowship from the German Federal Ministry of Education and Research, Hertie Foundation grants, Deutsche Forschungsgemeinschaft support, a National MS Society Career Transition Grant, and the Else‑Kröner‑Fresenius‑Foundation.
Key Questions Answered:
A: When muscles contract during aerobic exercise they release irisin into the bloodstream. This study shows irisin reaches the central nervous system and acts directly on neurons, helping to preserve their structure and synapses in the spinal cord, hippocampus, and retina during inflammatory assault.
A: Existing MS therapies are effective at lowering inflammation but less effective at preventing the progressive loss of neurons and synapses. Irisin represents a complementary strategy: rather than suppressing peripheral immunity, it provides direct neuroprotection that could help preserve function despite inflammatory injury.
A: No. The study demonstrates that irisin is a required mediator of exercise’s neuroprotective effects in a mouse model, but MS is complex and influenced by many factors. Exercise likely benefits patients through multiple mechanisms, and further work is needed to translate these molecular insights into clinical treatments.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full by the editorial team.
- Additional context was added by staff to clarify the study’s implications.
About this multiple sclerosis research news
Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image: Image credit: Neuroscience News
Original Research: Open access. Title: “The exercise hormone irisin has neuroprotective effects in a mouse model of multiple sclerosis.” Authors: Sina C. Rosenkranz et al. Journal: Nature Metabolism. DOI: 10.1038/s42255-026-01527-7
Abstract
The exercise hormone irisin has neuroprotective effects in a mouse model of multiple sclerosis
Aerobic exercise is a disease‑modifying intervention in multiple sclerosis that improves several progressive neurological symptoms. This study shows that irisin mediates exercise-induced neuroprotection in the experimental autoimmune encephalomyelitis (EAE) mouse model. Voluntary running protected against inflammation-driven neuronal degeneration, but these benefits were lost in mice lacking Fndc5/irisin. Peripheral administration of irisin increased plasma levels, reduced clinical severity and neuronal loss, and induced a neuron-specific protective gene program in the spinal cord. Irisin preserved synapses and mitochondrial function, likely through direct interactions with motor neurons, without broadly altering peripheral immune responses. These results identify irisin as a promising therapeutic candidate to directly protect neurons in inflammation-driven neurodegeneration such as MS.