At a glance
Irisin, a hormone released during exercise, appears to directly shield neurons from damage in a mouse model of multiple sclerosis.
An experimental gene therapy raised blood levels of the hormone, which in turn reduced clinical disability and limited neuron loss in the spinal cord, hippocampus, and retina of the mice.
Irisin’s protective effects appear to work independently of the immune system, pointing to a new strategy for MS drug development.
A new study offers clues as to why exercise can improve neurological symptoms in people with multiple sclerosis (MS).
Irisin — a hormone produced by muscles during exercise — reduced clinical symptoms and neuron loss in a mouse model of MS, found a team led by investigators from Harvard Medical School and University Medical Center Hamburg-Eppendorf (UKE) in Germany. Additionally, when the team deleted the gene encoding irisin, the protective effects of exercise disappeared.
The findings suggest that irisin can protect neurons from inflammation-driven neurodegeneration and that it does so by acting directly on the neurons rather than by suppressing the immune system. This uncovers a new way that exercise acts on MS and makes irisin a potential target for future MS therapies.
The results were published May 21 in Nature Metabolism.
“What we find particularly exciting is that [the work reveals] a fundamentally new mechanism by which exercise can influence neurodegeneration in MS,” said first author Sina Rosenkranz, head of the Behavioral Interventions group at the Institute for Neuroimmunology and Multiple Sclerosis (INIMS) at UKE and a former HMS postdoctoral fellow in the lab of co-senior author Christiane Wrann.
“We are optimistic that our study will open up further developments of irisin as a therapeutic for, in particular, progressive MS,” said Wrann, HMS associate professor of neurology at Massachusetts General Hospital and leader of the Program in Neuroprotection in Exercise at Mass General Brigham Neuroscience Institute. “Our findings strengthen the argument that irisin can help protect neurons in the context of multiple types of neurodegenerative diseases.”
The need for better MS treatments
MS is a chronic autoimmune disease in which the immune system attacks the myelin sheaths that insulate neurons in the brain and spinal cord, causing progressive neurological disability. Current therapies for MS reduce inflammation but do not prevent neurodegeneration, and no approved treatments directly target neurons to halt nerve cell loss. Research has shown that aerobic exercise can improve MS symptoms, but the exact mechanisms have been unknown.
Wrann and colleagues have previously shown that irisin can improve cognitive function and reduce neuroinflammation in mouse models of Alzheimer’s disease. The new study found similar neuroprotective effects in the mouse model of MS.
Mice that exercised on running wheels before developing MS and during the disease showed less neuronal loss and milder symptoms than sedentary animals. These benefits vanished entirely in mice with the gene encoding irisin deleted.
In a complementary set of experiments, deleting irisin again canceled out the protective effects of exercise, while delivering irisin through gene therapy rescued neurons and improved disease outcomes.
Direct action
Irisin reduced neuronal loss in three parts of the animals’ central nervous system — spinal cord, hippocampus, and retina — and reduced synapse loss and restored a neuroprotective gene program in spinal cord neurons.
Notably, irisin appeared to act directly on neurons rather than by dampening the immune response. No significant differences in immune cell activity were observed between irisin-treated and control animals. This neuronal pathway complements earlier work from HMS researchers showing that some benefits of exercise arise from changes in the immune system, underscoring that multiple biological mechanisms likely contribute to exercise’s protective effects in the brain.
“Interestingly, in the current study we did not find a direct suppressive effect of irisin on peripheral immunity, but rather direct neuroprotective effects,” said Ruxandra Sîrbulescu, co-senior author on the study and HMS assistant professor of neurology at Mass General.
The authors note that more research is needed to understand the precise mechanism by which irisin protects neurons. As the effects of exercise on MS are complex and likely involve multiple factors, irisin alone probably does not account for all of exercise’s benefits, they said.
Future work will also need to determine whether the findings translate to humans. The team plans to continue investigating the hormone’s effects and mechanisms in future studies.
Authorship, funding, disclosures
Additional 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 Ertaş, Marcel S. Woo, Vanessa Vieira, Samuel E. Honeycutt, James P. White, Gregory A. Wyant, Manuel A. Friese, and Peter A. Calabresi.
This study was supported by the National Institutes of Health (grants NS117694, AG062904, AG064580, AG072054, NS117598, NS041435, R56AG056664, T32AG07057); the Cure Alzheimer’s 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 Clinician-Scientist Fellowship from the Federal Ministry of Education and Research, Germany (iSTAR 01EO2106); the Gemeinnützige Hertie‑Stiftung (P1200012, P1250014); the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—project 523862973); a National MS Society Career Transition Grant (TA‑2104‑37423); and the Else Kröner‑Fresenius Foundation.
A full list of disclosures can be found in the paper.
