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.
We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by oligodendrocyte death, including MS.
The authors have none to report.
This work was supported by NIH-NINDS Training Award 5T32NS041218 to KAC, HHMI-supported Georgetown Hughes Undergraduate Scholars Program to KSC, and start up funds from Georgetown University to JKH. The authors would like to sincerely thank Dr. Dirk Isbrandt (University of Cologne) for providing us with Gamt +/- mice for these experiments. We would also like to thank Dr. Konstantina Psachoulia for training in surgical procedures and Dr. Thomas Coate for carefully reading this manuscript.
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