The Exercise Hormone Irisin Mediates Neuroprotective Effects in a Mouse Model of Multiple Sclerosis

Aerobic exercise has been considered a disease-modifying intervention in multiple sclerosis (MS) as it not only improves the physical fitness of people with MS but also ameliorates progressive neurological symptoms. However, the exact mechanisms are unknown, and currently, no drug is available that harnesses these therapeutic effects. The novel exercise hormone irisin, the secreted form of FNDC5 (fibronectin-domain III containing 5), is a prime candidate to mediate part of the neuroprotective exercise effects in MS as it is a crucial regulator of cognitive function in exercise, aging, and Alzheimer’s disease. Furthermore, irisin is neuroprotective in preclinical models of Alzheimer’s disease and Parkinson’s disease. Here, we show that voluntary wheel-running exercise leads to an ameliorated experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Peripheral delivery of irisin resulting in higher irisin plasma levels improves hippocampal and spinal cord clinical symptoms of EAE and reduces neurodegeneration. Interestingly, peripheral irisin does not alter peripheral and central immune response on a transcriptional level but induces neuroprotective gene programs in neurons, mainly associated with synapses and mitochondria. Accordingly, irisin and voluntary exercise resulted in a rescue of synaptic loss during EAE. Taken together, the exercise hormone irisin confers direct neuroprotective effects in an inflammation-driven neurodegenerative condition such as MS, thereby making it an attractive therapeutic target for MS.