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

Abstract

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.

Vigorous cool room treadmill training to improve walking ability in people with multiple sclerosis who use ambulatory assistive devices: a feasibility study

“…Participants rated three aspects of fatigue, [1] present level of energy (fatigue/energy/vitality sub-scale of SF-36 Health Survey), [2] severity of fatigue (FSS), and [3] impact of fatigue on everyday life (mFIS). Participants reported improved fatigue (36.4% or 14.3 point increase in energy levels on fatigue/energy/vitality sub-scale of SF-36 Health Survey) at post, which returned to pre levels at follow up (8.6 point increase from pre) ( Table 3) (Fig.…”

“…Cellular mechanisms contributing to neurodegeneration in MS include lack of trophic support to neurons and glia, chronic microglial activation, and mitochondrial injury induced by oxidative stress [2]. Several studies in animal models of MS suggest that exercise has direct protective and restorative effects by interacting with these mechanisms [3][4][5]. Evidence suggests that aerobic training promotes neuroplasticity by upregulating neurotrophins such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1) [6][7][8][9].…”

Inhibitory milieu at the multiple sclerosis lesion site and the challenges for remyelination

“…Studies within the lysolecithin model of demyelination have demonstrated that voluntary exercise increases oligodendrocyte cell number, remyelination, and reduces axonal injury (Jensen et al, ). At least part of this effect is via activation of the transcriptional co‐activator PGC1a (Jensen et al, ), although other signaling pathways (such as BDNF signaling) were also upregulated in the demyelinated tissue. This result is important, as it demonstrates that voluntary exercise enhances remyelination in a manner distinct from inflammation.…”

“…Importantly, although these studies suggest increased growth factor expression is protective, remyelination was never directly assessed. Studies within the lysolecithin model of demyelination have demonstrated that voluntary exercise increases oligodendrocyte cell number, remyelination, and reduces axonal injury (Jensen et al, 2018). At least part of this effect is via activation of the transcriptional co-activator PGC1a (Jensen et al, 2018) (Briken et al, 2016;Gold et al, 2003), suggesting that mechanisms of repair observed in animal models may also occur within human populations.…”

“…Studies within the lysolecithin model of demyelination have demonstrated that voluntary exercise increases oligodendrocyte cell number, remyelination, and reduces axonal injury (Jensen et al, 2018). At least part of this effect is via activation of the transcriptional co-activator PGC1a (Jensen et al, 2018) (Briken et al, 2016;Gold et al, 2003), suggesting that mechanisms of repair observed in animal models may also occur within human populations. These results suggest that elevating endogenous levels of neurotrophic factors may mimic the beneficial effects of exercise, which would provide a therapeutic alternative to sustained physical exercise.…”