Impaired mitochondrial respiration and decreased fatigue resistance followed by severe muscle weakness in skeletal muscle of mitochondrial DNA mutator mice

Key points Defective mitochondrial function has been shown to cause muscle weakness and exercise intolerance. We used a mouse model of premature ageing with defective proofreading of mitochondrial DNA (mtDNA): the mtDNA mutator mouse. Muscles of young (35 months) mtDNA mutator mice showed reduced endurance, which was caused by decreased mitochondrial ATP production accompanied by decreased levels of factors stimulating mitochondrial biogenesis. The dominant defect in muscles of old (11 months) mtDNA mutator mice was severe weakness, which was caused by decreased intracellular Ca2+ stores. These results underline two important aspects of mitochondria-to-nucleus signalling in skeletal muscle: (1) it fails to respond adequately to decreased mitochondrial ATP production in sedentary animals; and (2) it can induce decreased intracellular Ca2+ stores and hence muscle weakness. These results have implication for normal ageing and suggest that the decreased mitochondrial function induced by a sedentary lifestyle may predispose to muscle weakness later in life. 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 (35 months) and end-stage (11 months) mtDNA mutator mice were compared to age-matched control mice. Force and free myoplasmic [Ca2+] ([Ca2+]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 [Ca2+]i than control mice during induction of fatigue. Muscles of young mtDNA mutator mice showed decreased activities of citrate synthase and beta-hydroxyacyl-coenzyme A dehydrogenase, reduced expression of cytochrome c oxidase, and decreased expression of triggers of mitochondrial biogenesis (PGC-1 alpha, PPAR alpha, AMPK). Muscles from end-stage mtDNA mutator mice showed weakness under resting conditions with markedly decreased tetanic [Ca2+]i, force per cross-sectional area and protein expression of the sarcoplasmic reticulum Ca2+ 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.