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Several lines of research suggest that skeletal muscle mitochondrial volume and function decline with aging even in healthy individuals, and that the magnitude of this decline is larger in individuals with severe multimorbidity and those who are sedentary [8, 11]. Moreover, chronic exercise robustly increases mitochondrial capacity within muscles in older adults [12, 13], and exercise appears to more strongly correlate with mitochondrial content and performance than aging [14, 15]. However, the causal role of mitochondrial dysfunction in the genesis of sarcopenia has not been definitively established, with conflicting results across studies, remaining an area of intense investigation.

Animal studies have shown a decline in mitochondrial mass and number in skeletal muscle with aging, findings that have been confirmed in aging humans [16–21]. Most although not all studies conducted on muscle tissue using both confocal microscopy and electron microscopy have demonstrated that the number and shape of mitochondria, as well as the overall mitochondrial mass, decline with aging [22]. This is consistent with the discovery studies showing that mitochondrial transcripts and proteins are the most underrepresented classes of transcripts and proteins with older age in skeletal muscle [23]. Of note, proteomic studies indicate that the entire class of mitochondrial proteins becomes underrepresented with aging even in very healthy individuals, including structural proteins, proteins that are part of the electron transport chain (ETC) complexes, as well as critical enzymes for glycolysis and Krebs cycle (Figure 3.2) [24]. This is consistent with the idea that the whole mitochondrial mass declines with aging as percentage of muscle mass (or more precisely percentage of muscle proteins).

The decline of mitochondrial mass and function have important consequences for muscle health. Studies conducted with ³¹P MRI spectroscopy have shown that maximal ATP production (or maximal oxidative capacity) declines with aging even in relatively healthy individuals [25]. The decline of mitochondrial oxidative capacity with aging has been also confirmed “ex vivo;” by conducting respirometry on permeabilized muscle fibers from human biopsies [23, 26]. Such decline accounts for a significant percentage of the decline of muscle strength and walking speed observed with aging [27], is associated with fatigability [28] and sarcopenia [29, 30], and is a strong correlate of cardiorespiratory fitness [23, 26] and the development of insulin resistance [31].

Figure 3.2 Hypothesized mechanisms leading to mitochondrial dysfunction, decline in muscle performance, and mobility impairment.