Irisin, a hormone released during exercise, appears to directly shield neurons from damage in a mouse model of multiple sclerosis.
Photo Credit: Anupam Mahapatra
Scientific Frontline: Extended "At a Glance" Summary: Irisin and Neuroprotection in Multiple Sclerosis
The Core Concept: Irisin is a muscle-derived hormone released during aerobic exercise that directly shields neurons from damage and reduces clinical disability in preclinical models of multiple sclerosis (MS).
Key Distinction/Mechanism: Unlike current MS therapies that reduce inflammation by suppressing the immune system, irisin acts directly on central nervous system neurons to halt neurodegeneration without altering peripheral immune cell activity.
Major Frameworks/Components:
- Genetic Knockout Models: Deleting the gene responsible for encoding irisin in preclinical models completely erased the neuroprotective benefits typically conferred by exercise.
- Gene Therapy Recovery: Artificially elevating blood levels of irisin via experimental gene therapy rescued neurons and restored a neuroprotective gene expression program.
- Targeted CNS Protection: Irisin specifically reduced synapse and neuronal loss in critical anatomical regions, including the spinal cord, hippocampus, and retina.
Branch of Science: Neurology, Neuroimmunology, Neuroendocrinology, and Molecular Biology.
Future Application: The development of irisin-based pharmacological treatments or targeted gene therapies to actively halt progressive nerve cell loss in MS and potentially other neurodegenerative diseases.
Why It Matters: Existing MS treatments manage immune-driven inflammation but cannot stop ongoing neurodegeneration; irisin introduces a fundamentally new therapeutic mechanism that explains the physiological benefits of exercise at a molecular level.
A new study offers clues about 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, according to a team led by investigators from Harvard Medical School (HMS) and University Medical Center Hamburg-Eppendorf (UKE) in Germany. Additionally, when the team deleted the gene encoding irisin, the protective effects of exercise disappeared.
These 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 discovery uncovers a new way that exercise acts on MS and makes irisin a potential target for future MS therapies.
“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, an 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 were previously unknown.
Wrann and colleagues previously showed that irisin can improve cognitive function and reduce neuroinflammation in mouse models of Alzheimer’s disease. The new study found similar neuroprotective effects in a 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 lacking the gene that encodes irisin.
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—the spinal cord, hippocampus, and retina—and reduced synapse loss while restoring 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 of the study and an 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 underlying mechanisms.
Funding: 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.
Published in journal: Nature Metabolism
Title: The exercise hormone irisin has neuroprotective effects in a mouse model of multiple sclerosis
Authors: 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 Ertaş, Marcel S. Woo, Vanessa Vieira, Samuel E. Honeycutt, James P. White, Gregory A. Wyant, Manuel A. Friese, Peter A. Calabresi, Ruxandra F. Sîrbulescu, and Christiane D. Wrann
Source/Credit: Harvard Medical School | Mass General Brigham Communications
Edited by: Scientific Frontline
Reference Number: ns060426_03
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