Metabolomic analysis of exercise effects in the POLG mitochondrial DNA mutator mouse brain

NEUROBIOLOGY OF AGING

卷:36

Article

Clark-Matott, Joanne^1,2  Saleem, Ayesha^3,4  Dai, Ying^1,2  Shurubor, Yevgeniya⁵  Ma, Xiaoxing^3,4  Safdar, Adeel^1,2  Beal, Myron Flint⁵  Tarnopolsky, Mark^3,4  Simon, David K.^1,2 

[1] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA

[2] Harvard Univ, Sch Med, Boston, MA 02215 USA

[3] McMaster Univ, Med Ctr, Dept Pediat, Hamilton, ON, Canada

[4] McMaster Univ, Med Ctr, Dept Med, Hamilton, ON L8N 3Z5, Canada

[5] Cornell Univ, Weill Med Coll, Brain & Mind Inst, New York, NY 10021 USA

关键词: Aging;    Exercise;    Metabolism;    NAD;    Mitochondria;    DNA damage;   

DOI  :  10.1016/j.neurobiolaging.2015.07.020

来源: Elsevier

【 摘 要 】

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. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

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