Mitochondrial DNA Mutations Induce Mitochondrial Dysfunction, Apoptosis and Sarcopenia in Skeletal Muscle of Mitochondrial DNA Mutator Mice

Abstract

BackgroundAging results in a progressive loss of skeletal muscle, a condition known as sarcopenia. Mitochondrial DNA (mtDNA) mutations accumulate with aging in skeletal muscle and correlate with muscle loss, although no causal relationship has been established.Methodology/Principal FindingsWe investigated the relationship between mtDNA mutations and sarcopenia at the gene expression and biochemical levels using a mouse model that expresses a proofreading-deficient version (D257A) of the mitochondrial DNA Polymerase γ, resulting in increased spontaneous mtDNA mutation rates. Gene expression profiling of D257A mice followed by Parametric Analysis of Gene Set Enrichment (PAGE) indicates that the D257A mutation is associated with a profound downregulation of gene sets associated with mitochondrial function. At the biochemical level, sarcopenia in D257A mice is associated with a marked reduction (35–50%) in the content of electron transport chain (ETC) complexes I, III and IV, all of which are partly encoded by mtDNA. D257A mice display impaired mitochondrial bioenergetics associated with compromised state-3 respiration, lower ATP content and a resulting decrease in mitochondrial membrane potential (Δψm). Surprisingly, mitochondrial dysfunction was not accompanied by an increase in mitochondrial reactive oxygen species (ROS) production or oxidative damage.Conclusions/SignificanceThese findings demonstrate that mutations in mtDNA can be causal in sarcopenia by affecting the assembly of functional ETC complexes, the lack of which provokes a decrease in oxidative phosphorylation, without an increase in oxidative stress, and ultimately, skeletal muscle apoptosis and sarcopenia.

Exercise modulation of total antioxidant capacity (TAC): towards a molecular signature of healthy aging

“…It is well established that the massive free radical production in aging cells and organisms has been closely associated with higher rates of both DNA and RNA mutation (Robert et al 2010), confirming previous reports of an inverse association between DNA oxidation rates and longevity (Barja and Herrero et al 2000). It also has been demonstrated that mtDNA mutation impaired oxidative phosphorylation, without further free radical enhancement, leading to apoptosis of skeletal muscle cells and sarcopenia (Hiona et al 2010). By the same manner, detraining and sedentary behavior reduce mitochondrial biogenesis.…”

“…By the same manner, detraining and sedentary behavior reduce mitochondrial biogenesis. Thus, the aging subject frequently has lower muscle mitochondrial density and many senescent mitochondria which are related to reduced vital capacity, decreased physical fitness and to an increased risk of chronic and metabolic diseases (Ferrari 2008;Figueiredo et al 2008;Hiona et al 2010;Jackson et al 2010). Therein, positive associations have been observed between oxygen free radicals and both systolic and diastolic blood pressure values, whereas the association between ROS and arterial stiffness was only observed among hypertensive men (Kruger et al 2012).…”

The role of DNA exonucleases in protecting genome stability and their impact on ageing

“…The importance of exonucleolytic proofreading during mtDNA replication is clear from the phenotype of mice lacking mitochondrial polymerase proofreading through mutation of POLG, which show early-onset of many age-related phenotypes (Trifunovic et al 2004). 7 Mice carrying high levels of mitochondrial DNA mutation show sarcopenia and mitochondrial dysfunction in skeletal muscle (Hiona et al 2010), although this can be blunted by endurance exercise (Safdar et al 2011). They also show an accelerated age-related loss of retinal function (Kong et al 2011).…”

Apoptosis and necrosis mediate skeletal muscle fiber loss in age‐induced mitochondrial enzymatic abnormalities

“…Upregulation of the apoptotic pathway has been identified in premature aging models including mice lacking the antioxidant enzyme copper/zinc‐dependent superoxide dismutase (CuZnSOD or Sod1) that exhibit accelerated sarcopenia (Jang et al ., 2010), as well as interleukin‐10‐deficient mice that exhibit extreme frailty (Walston et al ., 2008). Increased levels of DNA laddering and caspase‐3 activity have been observed in transgenic mice expressing defective mitochondrial polymerase (Hiona et al ., 2010). …”