title: Metabolomic analysis of exercise effects in the POLG mitochondrial DNA mutator mouse brain.
abstract: Mitochondrial DNA (mtDNA) mutator mice express a mutated form of mtDNA polymerase gamma that results an accelerated accumulation of somatic mtDNA mutations in association with a premature aging phenotype. An exploratory metabolomic analysis of cortical metabolites in sedentary and exercised mtDNA mutator mice and wild-type littermate controls at 9-10 months of age was performed. Pathway analysis revealed deficits in the neurotransmitters acetylcholine, glutamate, and aspartate that were ameliorated by exercise. Nicotinamide adenine dinucleotide (NAD) depletion and evidence of increased poly(adenosine diphosphate-ribose) polymerase 1 (PARP1)activity were apparent in sedentary mtDNA mutator mouse cortex, along with deficits in carnitine metabolites and an upregulated antioxidant response that largely normalized with exercise. These data highlight specific pathways that are altered in the brain in association with an accelerated age-related accumulation of somatic mtDNA mutations. These results may have relevance to age-related neurodegenerative diseases associated with mitochondrial dysfunction, such as Alzheimer's disease and Parkinson's disease and provide insights into potential mechanisms of beneficial effects of exercise on brain function.
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. Electronic address: Jclark3@bidmc.harvard.edu.
authors: Joanne
authors: J
authors: Clark-Matott
authors: Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario, Canada; Department of Medicine, McMaster University Medical Center, Hamilton, Ontario, Canada.
authors: Ayesha
authors: A
authors: Saleem
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors: Ying
authors: Y
authors: Dai
authors: Brain and Mind Institute, Weill Medical College, Cornell University, New York, NY, USA.
authors: Yevgeniya
authors: Y
authors: Shurubor
authors: Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario, Canada; Department of Medicine, McMaster University Medical Center, Hamilton, Ontario, Canada.
authors: Xiaoxing
authors: X
authors: Ma
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors: Adeel
authors: A
authors: Safdar
authors: Brain and Mind Institute, Weill Medical College, Cornell University, New York, NY, USA.
authors: Myron Flint
authors: MF
authors: Beal
authors: Department of Pediatrics, McMaster University Medical Center, Hamilton, Ontario, Canada; Department of Medicine, McMaster University Medical Center, Hamilton, Ontario, Canada.
authors: Mark
authors: M
authors: Tarnopolsky
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors: David K
authors: DK
authors: Simon
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001224:Aspartic Acid / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002331:Carnitine / Q000378:metabolism; D004249:DNA Damage; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D005971:Glutamates / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D009154:Mutation; D009243:NAD / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004272:DNA, Mitochondrial; D005971:Glutamates; D018377:Neurotransmitter Agents; D009243:NAD; D001224:Aspartic Acid; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D000109:Acetylcholine; D002331:Carnitine
keywords: Aging; DNA damage; Exercise; Metabolism; Mitochondria; NAD