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 (PolgA) 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 (WT) 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 [ADP-ribose] polymerase 1 (PARP-1) 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.

Exosomes as Mediators of the Systemic Adaptations to Endurance Exercise

“…Several of these processes and other important components of aging can be linked to mitochondrial dysfunction, including telomere shortening, oxidative stress, inflammation, and even genomic instability (Safdar et al 2011a(Safdar et al , 2015Kolesar et al 2014). Training studies in murine models of aging further support the epidemiological data in showing that exercise training attenuates the ageassociated deleterious effects on mitochondria, antioxidant enzyme activity, and oxidative damage in skeletal muscle, adipose tissue, kidney, brain, and liver (Boveris and Navarro 2008;Sutherland et al 2009;Safdar et al 2011a;Clark-Matott et al 2015).…”

Determination of Coenzyme A and Acetyl-Coenzyme A in Biological Samples Using HPLC with UV Detection

“…CoA and acetyl-CoA were determined in cerebral cortices derived from 9–10-months-old WT and Mutant (Mut) mice. The Mut mice express a mutated form of mtDNA polymerase gamma (Polg) that results in mtDNA with a high burden of somatic mutations [ 24 ]. The Mut mice are a useful model for studies of age-related neurodegenerative diseases associated with mitochondrial dysfunction [ 24 ], such as Alzheimer disease and Parkinson disease.…”

“…The Mut mice express a mutated form of mtDNA polymerase gamma (Polg) that results in mtDNA with a high burden of somatic mutations [ 24 ]. The Mut mice are a useful model for studies of age-related neurodegenerative diseases associated with mitochondrial dysfunction [ 24 ], such as Alzheimer disease and Parkinson disease. These mice are also a good model for studying the beneficial effects of physiological activity (exercise) in neurodegeneration, and for preclinical assessment of possible therapeutic interventions [ 24 , 25 ].…”

Voluntary wheel running has no impact on brain and liver mitochondrial DNA copy number or mutation measures in the PolG mouse model of aging

“…In PolG mice, exercise has been reported to improve many aspects of premature aging, including restoration of mtDNA copy number in skeletal muscle, myocardium, and liver tissue, which facilitates restoration of brain metabolism, normalization of protein levels, and preservation of oocyte quality [4,[9][10][11]. Since the sole cause of premature aging in the PolG mouse model is an increase in mtDNA mutations, a decrease in mtDNA mutations would indicate an overall improvement and serve as a particularly reliable and relevant measure, or proxy, for mitochondrial health.…”