Summary: A neuroimmunology study uncovered the cellular mechanism decoding why exercise improves neurological symptoms in multiple sclerosis (MS). The research demonstrates that irisin, a hormone released by muscles during physical exertion, exerts a powerful, direct neuroprotective effect within the central nervous system.
By testing a mouse model of MS, investigators proved that irisin actively shields neurons from inflammation-driven neurodegeneration, decreases synaptic loss, and restores protective gene expression, providing a promising novel therapeutic bullseye for progressive forms of the disease.
Key Facts
- The Myelin Assault: Multiple sclerosis is a chronic, autoimmune-mediated neurodegenerative disease characterized by the immune system launching pathologically destructive attacks against the protective myelin sheaths surrounding neurons in the brain and spinal cord.
- The Neuroprotectant Hormone: Produced naturally by muscle tissue during exercise, the hormone irisin was found to drastically reduce clinical symptoms and stall the physical loss of neurons in experimental MS models.
- The Knockout Reversal: The protective benefits of physical exercise are fundamentally dependent on this endocrine pathway. When researchers genetically deleted irisin from the exercise models, the neuroprotective benefits vanished; conversely, injecting irisin back into the system rescued neurons and improved clinical outcomes.
- Tri-Compartmental Brain Shielding: Irisin successfully mitigated neuronal loss across three distinct zones of the central nervous system: the spinal cord, the hippocampus, and the retina. It also reduced the destruction of vital synaptic connections and restored a neuroprotective gene script.
- Bypassing Peripheral Immunity: Interestingly, co-senior author Dr. Ruxandra Sรฎrbulescu noted that irisin does not function by suppressing the peripheral immune system. Instead, it bypasses standard anti-inflammatory pathways to directly protect and stabilize the neurons themselves from neurodegeneration.
- Multifactorial Complexity: While irisin provides a definitive target for drug discovery, the authors emphasize that the clinical benefits of exercise in MS remain complex and likely involve an intricate symphony of multiple molecular factors working in tandem.
Source: Mass General
A new study offers clues as to why exercise can improve neurological symptoms in people with multiple sclerosis (MS).
The study, led by investigators fromย Mass General Brighamย and University Medical Center Hamburg-Eppendorf (UKE), examined levels of the exercise hormone irisin in a mouse model of multiple sclerosis.
Researchers found that irisin reduced both clinical symptoms and the loss of neurons in the experimental model. Additionally, when irisin was removed, the protective effects of exercise disappeared.
Taken together, the researchersโ findings suggest that irisin can protect neurons from inflammation-driven neurodegeneration, offering a potential target for future MS therapies.
Results are published inย Nature Metabolism.
โWe are optimistic that our study will open up further developments of irisin as a therapeutic for, in particular, progressive MS,โ said senior and corresponding authorย Christiane D. Wrann, DVM, PhD, a neuroscientist and leader of the Program in Neuroprotection in Exercise atย Mass General Brigham Neuroscience Instituteย and theย McCance Center for Brain Healthย at Massachusetts General Hospital.
โOur findings strengthen the argument that irisin can help protect neurons in the context of multiple types of neurodegenerative diseases.โ ย
MS is a chronic, autoimmune-mediated neurodegenerative disease in which the immune system attacks the myelin sheaths that swath neurons in the brain and spinal cord. Current therapies for MS reduce inflammation but do not adequately prevent neurodegeneration. Research from other groups has shown that aerobic exercise can improve MS symptoms, but the exact mechanisms have been unknown.
Wrann and colleagues have previously shown that the hormone irisin, produced by muscles during exercise, can improve cognitive function and neuroinflammation in mouse models ofย Alzheimerโs disease. In their new federally funded study of MS, researchers also found evidence of neuroprotective effects.
In the MS model, deleting irisin canceled out the protective effects of exercise while adding irisin back rescued neurons and improved disease outcomes. Irisin reduced neuronal loss in three central nervous system compartments: spinal cord, hippocampus, and retina, reduced loss of synapses and restored a neuroprotective gene program.
“What we find particularly exciting is that an exercise-induced molecule can directly protect neurons in a mouse model of multiple sclerosis, revealing a fundamentally new mechanism by which exercise can influence neurodegeneration in MS,โ said Sina C. Rosenkranz, MD, first author and head of the Behavioral Interventions group at the Institute for Neuroimmunology and Multiple Sclerosis (INIMS) at UKE. Rosenkranz is a former postdoctoral fellow in the Wrann lab.
โInterestingly, in the current study we did not find a direct suppressive effect of irisin on peripheral immunity, but rather direct neuroprotective effects,โ saidย Ruxandra F. Sรฎrbulescu, PhD,ย co-senior author on the study, a neuroimmunologist at Mass General Brigham Neuroscience Institute and leader of the Regenerative Medicine program at theย Vaccine and Immunotherapy Center.
The authors note that more research is needed to understand how irisinโs protective mechanism works. They also note that itโs important to remember that the benefits of exercise in multiple sclerosis are complex and likely involve multiple factors, not just irisin alone. The team plans to continue investigating the hormoneโs effects and mechanisms in future studies.
Authorship: In addition to Wrann, Rosenkranz, and Sรฎrbulescu, co-authors include 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 Ertaล, Marcel S. Woo, Vanessa Vieira, Samuel E. Honeycutt, James P. White, Gregory A. Wyant, Manuel A. Friese, and Peter A. Calabresi.
Disclosures: Wrann holds a patent related to irisin (WO2015051007A1). Wrann is an academic co-founder and consultant for Aevum Therapeutics. Wrann has a financial interest in Aevum Therapeutics, a company developing drugs which harness the protective molecular mechanisms of exercise to treat neurodegenerative and neuromuscular disorders. Wrann received honoraria from Novartis outside the scope of this work. Wrannโs interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. Rosenkranz has received speaker honoraria from Merck, Roche and Sanofi, all outside of this work. Calabresi has received consulting fees from Lilly and Novartis and is PI on a grant to JHU from Genentech. Woo received honoraria from Lilly and Eisai outside the scope of this work.
Funding: This work was supported in part by the National Institutes of Health (NS117694, AG062904, AG064580, AG072054, NS117598, NS041435, R56AG056664, T32AG07057); the Cure Alzheimerโs Fund; a SPARC Award from the McCance Center for Brain Health; the Hassenfeld Clinical Scholar Award; the Claflin Distinguished Scholar Award; the Boehringer Ingelheim Fonds travel grant; the Advanced ClinicianโScientist Fellowship from the Federal Ministry of Education and Research, Germany (iSTAR 01EO2106); the Gemeinnรผtzige HertieโStiftung (P1200012, P1250014); the Deutsche Forschungsgemeinschaft (DFG, German Research Foundationโproject 523862973); a National MS Society Career Transition Grant (TAโ2104โ37423); and the ElseโKrรถnerโFreseniusโFoundation.
Key Questions Answered:
A: It is a stunning display of cross-system biology. When you exercise, your working muscles act like an endocrine organ, secreting a specialized hormone called irisin straight into your bloodstream. Mass General Brigham and UKE discovered that irisin travels straight to the central nervous system. Instead of trying to fix your immune system, irisin goes directly to work on your nerve cells, acting like a structural shield that keeps neurons in your spinal cord, hippocampus, and retina from breaking down under an autoimmune attack.
A: Current MS therapies do a fantastic job of suppressing the immune system to quiet down localized inflammation, but they are notoriously poor at stopping the actual physical degeneration and death of neurons over time. That is why progressive MS remains so incredibly difficult to treat. Irisin represents a fundamentally new mechanism because it doesn’t suppress your peripheral immunity; instead, it acts as a direct neuroprotectant, offering a brand-new way to keep neurons alive and synapses intact when inflammation hits.
A: No, and it is vital to look at the full picture. While this mouse model study explicitly proves that irisin directly rescues neurons and is required to lock in the brain-boosting benefits of exercise, multiple sclerosis is an intricate, multifactorial disease. Working out triggers a highly complex symphony of biological changes throughout your body, meaning irisin isn’t acting entirely alone. The team is moving forward with deeper studies to translate these molecular discoveries into targeted therapies, specifically for progressive MS.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this multiple sclerosis research news
Author:ย Brandon Chase
Source:ย Mass General
Contact:ย Brandon Chase โ Mass General
Image:ย The image is credited to Neuroscience News
Original Research:ย Open access.
โThe exercise hormone irisin has neuroprotective effects in a mouse model of multiple sclerosisโ by Sina C. Rosenkranz, 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 Ertaล, Marcel S. Woo, Vanessa Vieira, Samuel E. Honeycutt, James P. White, Gregory A. Wyant, Manuel A. Friese, Peter A. Calabresi, Ruxandra F. Sรฎrbulescu & Christiane D. Wrann.ย 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 (MS) that ameliorates several progressive neurological symptoms in people with MS.
Here we show that the exercise hormone irisin mediates neuroprotective effects of exercise in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We demonstrate that voluntary free-wheel running exercise protects against inflammation-induced neurodegeneration in EAE, but these neuroprotective effects are abrogated in mice lackingย Fndc5/irisin.
Peripheral delivery of irisin increases irisin plasma levels and reduces both clinical symptoms and neuronal loss in EAE. Although peripheral irisin does not alter peripheral and central immune responses in EAE, it induces a direct neuroprotective gene programme in spinal cord neurons and preserves synapses and mitochondrial activity, probably through direct binding to motor neurons.
Taken together, these findings suggest that irisin induction in response to exercise confers direct neuroprotective effects in an inflammation-driven neurodegenerative condition, making it an attractive therapeutic candidate for MS.
