Creatine enhances mitochondrial-mediated oligodendrocyte survival following demyelinating injury
Chamberlain KA, Chapey KS, Nanescu SE, Huang JK
Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in ATP buffering, in oligodendrocyte function. We found that creatine directly increased mitochondrial ATP production in oligodendrocyte lineage cell cultures, and exerted robust protection on oligodendrocytes by preventing cell death in both naïve and lipopolysaccharide (LPS)-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase (Gamt) did not affect oligodendrocyte precursor cell (OPC) recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in CNS lesions. Remarkably, creatine administration into Gamt deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein (MBP) staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination.