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One of the best\u2010studied models is the prematurely aging mtDNA mutator mouse, which carries a homozygous knock\u2010in of a proofreading deficient version of the catalytic subunit of mtDNA polymerase\u2010\u03b3 (<jats:italic>PolgA<\/jats:italic>). We investigated how voluntary exercise affects the progression of aging phenotypes in this mouse, focusing on mitochondrial and protein homeostasis in both brain and peripheral tissues. Voluntary exercise significantly ameliorated several aspects of the premature aging phenotype, including decreased locomotor activity, alopecia, and kyphosis, but did not have major effects on the decreased lifespan of mtDNA mutator mice. Exercise also decreased the mtDNA mutation load. In\u2010depth tissue proteomics revealed that exercise normalized the levels of about half the proteins, with the majority involved in mitochondrial function and nuclear\u2013mitochondrial crosstalk. There was also a specific increase in the nuclear\u2010encoded proteins needed for the tricarboxylic acid cycle and complex II, but not in mitochondrial\u2010encoded oxidative phosphorylation proteins, as well as normalization of enzymes involved in coenzyme Q biosynthesis. Furthermore, we found tissue\u2010specific alterations, with brain coping better as compared to muscle and with motor cortex being better protected than striatum, in response to mitochondrial dysfunction. We conclude that voluntary exercise counteracts aging in mtDNA mutator mice by counteracting protein dysregulation in muscle and brain, decreasing the mtDNA mutation burden in muscle, and delaying overt aging phenotypes.<\/jats:p>","DOI":"10.1111\/acel.13029","type":"journal-article","created":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T08:01:01Z","timestamp":1567756861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Voluntary exercise normalizes the proteomic landscape in muscle and brain and improves the phenotype of progeroid mice"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3879-4817","authenticated-orcid":false,"given":"Jaime M.","family":"Ross","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Biomedicum Karolinska Institutet Stockholm Sweden"},{"name":"Department of Genetics Blavatnik Institute, Paul F. 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