title: Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury.
abstract: 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 adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase (Gamt) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration intoGamt-deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein 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.SIGNIFICANCE STATEMENTWe 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 multiple sclerosis.
authors.affiliation: Department of Biology and.|Interdisciplinary Program in Neuroscience, Georgetown University, Washington, District of Columbia 20057.
authors.forename: Kelly A
authors.identifier: 0000-0002-4793-8966
authors.initials: KA
authors.lastname: Chamberlain
authors.affiliation: Department of Biology and.
authors.forename: Kristen S
authors.identifier: 0000-0001-7926-0873
authors.initials: KS
authors.lastname: Chapey
authors.affiliation: Department of Biology and.
authors.forename: Sonia E
authors.initials: SE
authors.lastname: Nanescu
authors.affiliation: Department of Biology and jeffrey.huang@georgetown.edu.|Interdisciplinary Program in Neuroscience, Georgetown University, Washington, District of Columbia 20057.
authors.forename: Jeffrey K
authors.identifier: 0000-0003-0996-9451
authors.initials: JK
authors.lastname: Huang
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003401:Creatine / Q000096:biosynthesis* / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*
chemical_list: D003401:Creatine
keywords: apoptosis; creatine; demyelination; guanidinoacetate-methyltransferase; oligodendrocyte; regeneration