Multimodal enhancement of remyelination by exercise with a pivotal role for oligodendroglial PGC1a

Remyelination is a multistep regenerative process that results in the reformation of myelin sheaths around demyelinated axons and is a critical therapeutic target. Here we show that immediate access to a running wheel following toxin-induced demyelination in mice enhances oligodendrogenesis, myelin thickness, and the proportion of remyelinated axons. RNA-sequencing suggests broad activation of pro-remyelination pathways including phagocytosis by exercise and highlights peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) activation. Our study demonstrates that physical activity is an integrative means to enhance remyelination and details a multimodal mechanism including the pivotal PGC1a-dependent enhancement of myelin thickness. We investigated the effect of physical exercise on remyelination using lysolecithin model of toxin induced demyelination. Voluntary exercise was introduced via unrestricted access to monitored running wheel. Control animals were subjected to the same conditions except the running wheel was locked. Generation of new olygodendrocytes was evaluated immunohistochemically using pan-olygodendrocyte lineage marker Olig2. The level remyelination was directly examined by immunohistochemical labeling of myelin basic protein (MBP) and additionally by electron microscopy. Transcriptome profiling of lesion sites was conducted using RNA-seq. The lesion tissue samples were obtained using laser micro dissections.