Oxidative stress and Nrf2 signaling in McArdle disease.

McArdle disease (MD) is a metabolic myopathy due to myophosphorylase deficiency, which leads to a severe limitation in the rate of adenosine triphosphate (ATP) resynthesis. Compensatory flux through the myoadenylate deaminase > > xanthine oxidase pathway should result in higher oxidative stress in skeletal muscle; however, oxidative stress and nuclear factor erythroid 2-related factor 2 (Nrf2) mediated antioxidant response cascade in MD patients have not yet been examined. We show that MD patients have elevated muscle protein carbonyls and 4-hydroxynonenal (4-HNE) in comparison with healthy, age and activity matched controls (P < 0.05). Nuclear abundance of Nrf2 and Nrf2-antioxidant response element (ARE) binding was also higher in MD patients compared with controls (P < 0.05). The expressions of Nrf2 target genes were also higher in MD patients vs. controls. These observations suggest that MD patients experience elevated levels of oxidative stress, and that the Nrf2-mediated antioxidant response cascade is up-regulated in skeletal muscle to compensate.

Markers of skeletal muscle mitochondrial function and lipid accumulation are moderately associated with the homeostasis model assessment index of insulin resistance in obese men.

Lower skeletal muscle mitochondrial oxidative phosphorylation capacity (OXPHOS) and intramyocellular lipid (IMCL) accumulation have been implicated in the etiology of insulin resistance (IR) in obesity. The purpose of this study was to examine the impact of endurance exercise on biochemical and morphological measures of IMCL and mitochondrial content, and their relationship to IR in obese individuals. We examined mitochondrial content (subunit protein abundance and maximal activity of electron transport chain enzymes), IMCL/mitochondrial morphology in both subsarcolemmal (SS) and intermyofibrillar (IMF) regions by transmission electron microscopy, and intracellular lipid metabolites (diacylglycerol and ceramide) in vastus lateralis biopsies, as well as, the homeostasis model assessment index of IR (HOMA-IR) prior to and following twelve weeks of an endurance exercise regimen in healthy age- and physical activity-matched lean and obese men. Obese men did not show evidence of mitochondrial OXPHOS dysfunction, disproportionate IMCL content in sub-cellular regions, or diacylglycerol/ceramide accretion despite marked IR vs. lean controls. Endurance exercise increased OXPHOS and mitochondrial size and density, but not number of individual mitochondrial fragments, with moderate improvements in HOMA-IR. Exercise reduced SS IMCL content (size, number and density), increased IMF IMCL content, while increasing IMCL/mitochondrial juxtaposition in both regions. HOMA-IR was inversely associated with SS (r = -0.34; P = 0.051) and IMF mitochondrial density (r = -0.29; P = 0.096), IMF IMCL/mitochondrial juxtaposition (r = -0.30; P = 0.086), and COXII (r = -0.32; P = 0.095) and COXIV protein abundance (r = -0.35; P = 0.052); while positively associated with SS IMCL size (r = 0.28; P = 0.119) and SS IMCL density (r = 0.25; P = 0.152). Our findings suggest that once physical activity and cardiorespiratory fitness have been controlled for, skeletal muscle mitochondrial and IMCL profile in obesity may only partially contribute to the development of IR.

Monocarboxylate transporters and mitochondrial creatine kinase protein content in McArdle disease.

McArdle disease (MD) is a metabolic myopathy due to myophosphorylase deficiency. We examined monocarboxylate transporters (MCT) and creatine kinase (CK) protein content in skeletal muscle from MD patients and age-matched controls to evaluate potential cellular adaptations that compensate for the loss of glycogenolysis. Our findings of higher MCT1 and mitochondrial CK suggest that proteins related to extra-muscular fuel uptake and intra-muscular energy transduction are up-regulated without change in mitochondrial mass in MD patients.

Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice.

A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.