No decline in skeletal muscle oxidative capacity with aging in long-term calorically restricted rats: effects are independent of mitochondrial DNA integrity.
ABSTRACT We investigated if calorie restriction (CR) preserved skeletal muscle oxidative capacity with aging after accounting for life span extension by CR, and determined if mitochondrial content, mitochondrial DNA integrity, and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) were involved. Ad libitum-fed (AL) and CR animals representing young adult, late middle age, and senescence were studied. Whereas citrate synthase and complex IV activities were lower in plantaris and gastrocnemius muscle of young adult CR animals, in contrast to the 15%-40% decline in senescent AL animals, there was no decline with aging in CR animals. There was no decline in citrate synthase protein in gastrocnemius with aging in either group, suggesting that CR preserves oxidative capacity with aging by protecting mitochondrial function rather than content. This protection was independent of mitochondrial DNA damage between groups. However, there was a slower decline in PGC-1alpha gene expression with aging in CR versus AL animals, suggesting a better maintenance of mitochondrial biogenesis with aging in CR animals.
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ABSTRACT: The responses to bacterial lipopolysaccharide (LPS) damage mitochondria by generating oxidative stress within the organelles. We postulated that LPS damages heart mitochondrial DNA and protein by oxidation, and that this is recovered by oxidative mechanisms of mitochondrial biogenesis. Systemic crude E. coli LPS administration decreased mtDNA copy number and mtDNA gene transcription in rat heart caused by oxidant deletion of mtDNA. The fall in copy number was reflected in proteomic expression of several mitochondria-encoded subunits of Complexes I, IV, and V. Recovery of mtDNA copy number involved biogenesis as indicated by mitochondrial transcription factor A (Tfam) and DNA polymerase-gamma expression. The transcriptional response also included nuclear accumulation of peroxisome proliferator-activated receptor-gamma co-activator 1 (PGC-1) and mRNA expression for redox-regulated nuclear respiratory factors (NRF-1 and -2). These novel findings disclose a duality of reactive oxygen species (ROS) effect in the heart's response to LPS in which oxidative mitochondrial damage is opposed by oxidant stimulation of biogenesis.Cardiovascular Research 12/2004; 64(2):279-88. · 5.94 Impact Factor
- Science 04/1917; 45(1160):294-5. · 31.03 Impact Factor
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ABSTRACT: A progressive decline in muscle performance in the rapidly expanding aging population is causing a dramatic increase in disability and health care costs. A decrease in muscle endurance capacity due to mitochondrial decay likely contributes to this decline in muscle performance. We developed a novel stable isotope technique to measure in vivo rates of mitochondrial protein synthesis in human skeletal muscle using needle biopsy samples and applied this technique to elucidate a potential mechanism for the age-related decline in the mitochondrial content and function of skeletal muscle. The fractional rate of muscle mitochondrial protein synthesis in young humans (24 +/- 1 year) was 0.081 +/- 0.004%.h-1, and this rate declined to 0.047 +/- 0.005%.h-1 by middle age (54 +/- 1 year; P < 0.01). No further decline in the rate of mitochondrial protein synthesis (0.051 +/- 0.004%.h-1) occurred with advancing age (73 +/- 2 years). The mitochondrial synthesis rate was about 95% higher than that of mixed protein in the young, whereas it was approximately 35% higher in the middle-aged and elderly subjects. In addition, decreasing activities of mitochondrial enzymes were observed in muscle homogenates (cytochrome c oxidase and citrate synthase) and in isolated mitochondria (citrate synthase) with increasing age, indicating declines in muscle oxidative capacity and mitochondrial function, respectively. The decrease in the rates of mitochondrial protein synthesis is likely to be responsible for this decline in muscle oxidative capacity and mitochondrial function. These changes in muscle mitochondrial protein metabolism may contribute to the age-related decline in aerobic capacity and muscle performance.Proceedings of the National Academy of Sciences 12/1996; 93(26):15364-9. · 9.74 Impact Factor