Multimodal Enhancement of Remyelination by Exercise with a Pivotal Role for Oligodendroglial PGC1α

Summary 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, the rate of remyelination, 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 co-activator 1-alpha (PGC1α) activation. By immunohistochemistry and cell type-specific conditional deletion, we confirmed PGC1α within oligodendrocytes as a transiently expressed factor required for the rate of myelin thickening by exercise. We validated the exercise-enhanced clearance of inhibitory lipid debris from lesions. Finally, exercise works in parallel with the remyelinating medication clemastine to produce complete remyelination of lesions. Our study demonstrates physical activity as an integrative means to enhance remyelination and details a multimodal mechanism including the pivotal PGC1α-dependent enhancement of myelin thickness.