title: Increased mitochondrial biogenesis in muscle improves aging phenotypes in the mtDNA mutator mouse.
abstract: Aging is an intricate process that increases susceptibility to sarcopenia and cardiovascular diseases. The accumulation of mitochondrial DNA (mtDNA) mutations is believed to contribute to mitochondrial dysfunction, potentially shortening lifespan. The mtDNA mutator mouse, a mouse model with a proofreading-deficient mtDNA polymerase γ, was shown to develop a premature aging phenotype, including sarcopenia, cardiomyopathy and decreased lifespan. This phenotype was associated with an accumulation of mtDNA mutations and mitochondrial dysfunction. We found that increased expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a crucial regulator of mitochondrial biogenesis and function, in the muscle of mutator mice increased mitochondrial biogenesis and function and also improved the skeletal muscle and heart phenotypes of the mice. Deep sequencing analysis of their mtDNA showed that the increased mitochondrial biogenesis did not reduce the accumulation of mtDNA mutations but rather caused a small increase. These results indicate that increased muscle PGC-1α expression is able to improve some premature aging phenotypes in the mutator mice without reverting the accumulation of mtDNA mutations.
authors.affiliation: Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Lloye M
authors.initials: LM
authors.lastname: Dillon
authors.forename: Siôn L
authors.initials: SL
authors.lastname: Williams
authors.forename: Aline
authors.initials: A
authors.lastname: Hida
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Peacock
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
authors.forename: Joy
authors.initials: J
authors.lastname: Lincoln
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D004272:DNA, Mitochondrial; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors