期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：11330-11334
DOI：10.1073/pnas.1514844112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceApproximately 40% of Americans over the age of 65 suffer from impaired glucose tolerance or type 2 diabetes; however, the pathogenesis of aging-associated reductions in glucose metabolism is poorly understood. Aging is associated with muscle insulin resistance, increased intramyocellular fat content, and reductions in rates of muscle mitochondrial activity. To further examine the potential role of age-associated alterations in mitochondrial metabolism, we applied a novel method to assess muscle specific rates of mitochondrial glucose and fat oxidation and demonstrate that aging is also associated with a marked inability of mitochondria to switch from lipid to glucose oxidation on insulin stimulation, which may further contribute to dysregulated glucose and lipid metabolism in the elderly. Previous studies have implicated age-associated reductions in mitochondrial oxidative phosphorylation activity in skeletal muscle as a predisposing factor for intramyocellular lipid (IMCL) accumulation and muscle insulin resistance (IR) in the elderly. To further investigate potential alterations in muscle mitochondrial function associated with aging, we assessed basal and insulin-stimulated rates of muscle pyruvate dehydrogenase (VPDH) flux relative to citrate synthase flux (VCS) in healthy lean, elderly subjects and healthy young body mass index- and activity-matched subjects. VPDH/VCS flux was assessed from the 13C incorporation from of infused [1-13C] glucose into glutamate [4-13C] relative to alanine [3-13C] assessed by LC-tandem MS in muscle biopsies. Insulin-stimulated rates of muscle glucose uptake were reduced by 25% (P < 0.01) in the elderly subjects and were associated with [~]70% (P < 0.04) increase in IMCL, assessed by 1H magnetic resonance spectroscopy. Basal VPDH/VCS fluxes were similar between the groups (young: 0.20 {+/-} 0.03; elderly: 0.14 {+/-} 0.03) and increased approximately threefold in the young subjects following insulin stimulation. However, this increase was severely blunted in the elderly subjects (young: 0.55 {+/-} 0.04; elderly: 0.18 {+/-} 0.02, P = 0.0002) and was associated with an [~]40% (P = 0.004) reduction in insulin activation of Akt. These results provide new insights into acquired mitochondrial abnormalities associated with aging and demonstrate that age-associated reductions in muscle mitochondrial function and increased IMCL are associated with a marked inability of mitochondria to switch from lipid to glucose oxidation during insulin stimulation.
