Decline in Skeletal Muscle Mitochondrial Function Associated with Aging

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Impaired oxidative phosphorylation by skeletal muscle mitochondria has been postulated to contribute to age-associated insulin resistance and fat accumulation within skeletal muscle [3]. This impaired mitochondrial functional capacity associated with aging has been attributed to a reduced mitochondrial content, as reflected by lower mtDNA content [50]. Many age-related declines in physiological function can be partially attributed to mitochondria dysfunction [51]. There is a significant loss in the number of muscle fibers as well as biochemical and morphological abnormalities in aging skeletal muscle [52,53]. Age-related muscle wasting, muscle weakness, and reduced aerobic capacity result in many metabolic disorders and diminished physical performance in humans [54-56]. The specific mechanisms leading to the age-related changes are currently unknown. Mitochondria are primary sites of reactive oxygen species formation that causes progressive damage to mtDNA and proteins [53,57]. Increased prevalence of mtDNA mutations [58,59], decreased mtDNA abundance [60,61], and progressive decline in mitochondrial respiratory chain function [62,63] have been proposed as underlying causes of mitochondrial dysfunction in aging. This finding is based on the hypothesis that cumulative oxidative damage could be the cause of aging [64]. Furthermore, oxidative damage has been associated with increased mtDNA mutations and deletions in older muscles [43,58]. The importance of mtDNA damage has recently been demonstrated in mice in which accumulation of mtDNA mutations resulted in accelerated aging [65]. Oxidative damage to proteins, lipids, and other cellular components may also affect the function of aging cells [66]. The rate of synthesis of contractile and mitochondrial proteins in human skeletal muscle was shown to decline with advancing age and this may alter muscle metabolic capacity in older people [54-56]. The activity of oxidative enzymes and content mRNA transcripts encoding mitochondrial proteins are also reduced in older muscle [47, 55, 60, 61]. Content and function of specific proteins in muscle depends on protein synthesis and breakdown. Mitochondrial protein synthesis declines with age in human muscle [55]. This decline may be due to reduced mRNA template availability because both COX3 and COX4 transcript levels decline significantly as we age [47,61]. It has recently been reported that mRNA abundance of three nuclear-derived transcription factors that regulate mitochondrial biogenesis, PGC-1a, NRF-1, and TFAM, do not change with age in human muscle. These findings demonstrate that despite age-related functional decline, skeletal muscle capacity for mitochondrial biogenesis remains high in older muscle when stimulated by regular aerobic exercise. Hence, further work on the effect of aging on the action of these and other nuclear signals that regulate mitochondrial biogenesis is needed. These studies collectively raise the question of whether age-related mitochondrial defects are the result of normal aging or conversely, whether they are at least partially acquired through lifestyle and factors other than aging per se.

A robust improvement in skeletal muscle mitochondrial content and function was found in elderly men and women in response to a program of moderate intensity physical exercise [47,48]. Kelley et al. [7] observed an impaired bioenergetic capacity of skeletal muscle mitochondria in type 2 diabetes and obesity, including smaller mitochondria and reduced electron transport chain activity. The electron transport chain activity in the healthy older participants at baseline was three-fold less than that observed for younger lean individuals but similar to that seen in middle-aged obese participants without type 2 diabetes [67]. In particular, the lower electron transport chain activity in these older men and women was more pronounced in sub-sarcolemmal mitochondria than in inter-myofibrillar mitochondria. In these individuals, exercise training improved mitochondrial content and mitochondrial function; however, this improvement was more pronounced in sub-sarcolemmal than in inter-myofibrillar mitochondria [48]. Sub-sarcolemmal mitochondria likely provide energy for cellular processes of substrate transport and cell signaling in skeletal muscle [68], and exhibit higher rates of fatty acid oxidation [69]. Thus, sub-sarcolemmal mitochondria may be specifically linked to physical inactivity, low oxidative capacity, and insulin resistance. Further work on the functional significance of how different mitochondrial subpopulations in skeletal muscle respond to exercise stimulation might provide new insight for designing specific interventions, including exercise, for the prevention and treatment of skeletal muscle functional changes associated with aging.

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