Sina C. Rosenkranz, Joana F. da Rocha, Luis Moreira, Pius Schlachter, Jasmina Bier, Kaela Healy, Daniela Neves Da Silva, Mohamed Iqbal, Marjan Gharagozloo, Yueyue Xiong, Matthew A. Murphy, Helena C. Lichtenfeld, Lukas Raich, Michaela Schweizer, Asude Ertas, Marcel S. Woo, Vanessa Vieira, Samuel E. Honeycutt, James P. White, Gregory A. Wyant, Manuel A. Friese, Peter A. Calabresi, Ruxandra F. Sîrbulescu, Christiane D. Wrann
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.