USING PROTEOMICS TO ELUCIDATE HOW VOLUNTARY EXERCISE COMBATS AGING PHENOTYPES IN MTDNA MUTATOR MICE. (11th November 2018)

• Record Type: Journal Article
• Authors: Ross, J M; Coppotelli, Giuseppe; Branca, R; Lehtiö, J; Sinclair, D; Olson, Lars
• Is Part Of: Innovation in aging. Volume 2(2018)Supplement 1
• Page Start: 334
• Page End: 334
• Publication Date: 2018-11-11
• Subjects: Aging -- Periodicals; Gerontology -- Periodicals; 612.67
• DOI: 10.1093/geroni/igy023.1223
• Languages: English
• ISSNs: 2399-5300

Abstract

Abstract: Accumulation of mitochondrial DNA (mtDNA) mutations resulting in mitochondrial dysfunction has been heavily implicated in aging and age-related diseases, such as Alzheimer's and Parkinson's disease. To study the effects of severe progressive mitochondrial dysfunction, homozygous knock-in mice expressing a proofreading deficient version of the nucleus-encoded catalytic subunit (PolgA) of mtDNA polymerase-γ have been developed. Using this robust model of premature aging, the mtDNA mutator mouse, we investigated the underlying molecular mechanisms that cause voluntary endurance exercise, i.e. free access to running wheels, to slow the progression of aging phenotypes, focusing on mitochondrial and protein homeostasis in both brain and peripheral tissues. A novel running wheel system that is compatible with standard mouse home cages was used, thus allowing for long-term studies. We found that exercise does significantly ameliorate several aspects of the premature aging phenotypes in mtDNA mutator mice, such as locomotor activity, alopecia, kyphosis, etc., but does not elongate lifespan. We also used a wide analytic approach, peptide high-resolution isoelectric focusing (HiRIEF) coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS), to analyze changes induced by exercise at the protein level in key brain regions and peripheral tissues. Surprisingly, we found that exercise was able to normalize levels of about 50% of the dysregulated proteins found in sedentary mtDNA mutator mice. The majority of these exercise-induced improvements concerned mitochondrial function and nuclear-mitochondrial crosstalk. Identifying therapies and understanding how they might combat mitochondrial deficiencies will provide valuable insights into the aging process.