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 lacking 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.
Authors
- Marjan Gharagozloo (ORCID: https://orcid.org/0000-0002-2166-4012)
- Michaela Schweizer (ORCID: https://orcid.org/0000-0001-5062-328X)
- Gregory A. Wyant (ORCID: https://orcid.org/0000-0002-4665-2405)
- Vanessa Vieira (ORCID: https://orcid.org/0000-0002-0205-9669)
- Matthew A. Murphy
- Mohamed Iqbal (ORCID: https://orcid.org/0000-0002-5094-0717)
- Peter A. Calabresi (ORCID: https://orcid.org/0000-0002-7776-6472)
- Ruxandra F. Sîrbulescu (ORCID: https://orcid.org/0000-0001-7905-1713)
- Daniela Neves Da Silva
- Jasmina Bier (ORCID: https://orcid.org/0000-0003-2330-0797)
- Lukas Raich (ORCID: https://orcid.org/0009-0001-6725-1918)
- Yueyue Xiong
- James P. White (ORCID: https://orcid.org/0000-0002-1422-5812)
- Asude Ertas
- Pius Schlachter
- Kaela Healy
- Marcel S. Woo
- Sina C. Rosenkranz
- Manuel A. Friese (ORCID: https://orcid.org/0000-0001-6380-2420)
- Joana F. da Rocha (ORCID: https://orcid.org/0000-0002-2496-4061)
- Helena C. Lichtenfeld
- Samuel E. Honeycutt
- Christiane D. Wrann (ORCID: https://orcid.org/0000-0001-6066-8799)
- Luis Moreira
Institutions
- Harvard University (US)
- Johns Hopkins University (US)
- Universität Hamburg (DE)
- Duke University (US)
- Johns Hopkins Medicine (US)
- Massachusetts General Hospital (US)
- University Medical Center Hamburg-Eppendorf (DE)
- Mass General Brigham (US)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-05-21
- DOI
- https://doi.org/10.1038/s42255-026-01527-7
- Citations
- 1
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 15.30