title: Impaired mitochondrial respiration and decreased fatigue resistance followed by severe muscle weakness in skeletal muscle of mitochondrial DNA mutator mice.
abstract: Mitochondrial dysfunction can drastically impair muscle function, with weakness and exercise intolerance as key symptoms. Here we examine the time course of development of muscle dysfunction in a mouse model of premature ageing induced by defective proofreading function of mitochondrial DNA (mtDNA) polymerase (mtDNA mutator mouse). Isolated fast-twitch muscles and single muscle fibres from young (3-5 months) and end-stage (11 months) mtDNA mutator mice were compared to age-matched control mice. Force and free myoplasmic [Ca(2+)] ([Ca(2+)](i)) were measured under resting conditions and during fatigue induced by repeated tetani. Muscles of young mtDNA mutator mice displayed no weakness in the rested state, but had lower force and [Ca(2+)](i) than control mice during induction of fatigue. Muscles of young mtDNA mutator mice showed decreased activities of citrate synthase and β-hydroxyacyl-coenzyme A dehydrogenase, reduced expression of cytochrome c oxidase, and decreased expression of triggers of mitochondrial biogenesis (PGC-1α, PPARα, AMPK). Muscles from end-stage mtDNA mutator mice showed weakness under resting conditions with markedly decreased tetanic [Ca(2+)](i), force per cross-sectional area and protein expression of the sarcoplasmic reticulum Ca(2+) pump (SERCA1). In conclusion, fast-twitch muscles of prematurely ageing mtDNA mutator mice display a sequence of deleterious mitochondrial-to-nucleus signalling with an initial decrease in oxidative capacity, which was not counteracted by activation of signalling to increase mitochondrial biogenesis. This was followed by severe muscle weakness in the end stage. These results have implication for normal ageing and suggest that decreased mitochondrial oxidative capacity due to a sedentary lifestyle may predispose towards muscle weakness developing later in life.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: Niklas
authors.initials: N
authors.lastname: Ivarsson
authors.forename: Andrés
authors.initials: A
authors.lastname: Hernández
authors.forename: Andreas
authors.initials: A
authors.lastname: Fahlström
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Cheng
authors.forename: Shi-Jin
authors.initials: SJ
authors.lastname: Zhang
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bruton
authors.forename: Brun
authors.initials: B
authors.lastname: Ulfhake
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
mesh_terms: D019588:Aging, Premature / Q000503:physiopathology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008931:Mitochondria, Muscle / Q000502:physiology*; D018763:Muscle Fatigue / Q000502:physiology*; D018908:Muscle Weakness / Q000503:physiopathology*; D018482:Muscle, Skeletal / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000502:physiology
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D002118:Calcium