Skeletal muscle health is dependent on the optimal function of its mitochondria. With advancing age, decrements in numerous mitochondrial variables are evident in muscle. Part of this decline is due to reduced physical activity, whereas the remainder appears to be attributed to age-related alterations in mitochondrial synthesis and degradation. Exercise is an important strategy to stimulate mitochondrial adaptations in older individuals to foster improvements in muscle function and quality of life.Heather N. Carter, Chris C. W. The process of aging exploits the malleable nature of skeletal muscle. The age-related loss of muscle mass was termed sarcopenia, based on the Greek (sarx, flesh) and (penia, poverty) in 1988 (139). Accompanying this loss are profound architectural and molecular changes that alter muscle quality and are manifested in functional limitations. Decreases in muscle fiber number as well as fiber cross-sectional area are both contributing factors to sarcopenia (92) and consequently adversely affect force production (strength) (46, 63) and endurance of the older individual (12). Muscle mass typically peaks in the mid-20s (12, 34,92), and thereafter several distinct phases of muscle loss have been identified. In the third to fifth decade of life, a slow rate of muscle mass loss is noted, amounting to ϳ10% in total (34,92). In later adulthood (Ͼ45 yr), the rate of muscle loss increases, with appraisals ranging between 0.5 and 1.4% per year (12, 34,69). Even more dramatic changes are noted beyond the sixth decade of life. Along with the functional impairments imposed by sarcopenia, are the associated escalations in health care costs, along with coincident rises in metabolic diseases (e.g., Type 2 diabetes, obesity) and a greater risk of falls (67). In the U.S., it is expected that those 65 years of age and over will comprise ϳ20% of the population, or ϳ72 million people, by the year 2030 (20). Since the proportion of older adults is increasing, continued research into the mechanisms of muscle loss is warranted, along with the investigation of therapeutic strategies that can mitigate muscle atrophy during aging. Mitochondria have been implicated as potential mediators of sarcopenia. Recently, it has been suggested that dysfunction of these organelles can be considered a feature of aging (105). However, considerable controversy exists regarding the extent to which muscle mitochondria may be dysfunctional with aging, and thereby contribute to the loss of this tissue. Thus the purpose of this review is to examine the literature with respect to mitochondrial content and function in muscle with advancing age, and provide a perspective on the effectiveness of endurance/aerobic exercise as an intervention for mitochondrial biogenesis and muscle homeostasis in older individuals. Structural Features of Muscle Relevant to SarcopeniaIn young, healthy individuals, skeletal muscle comprises ϳ40% of total body mass and is important for locomotion and whole body metabolism. Myosin ATPase histochemistry and electrop...

Skeletal muscle exhibits deficits in mitochondrial quality with age. Central to the maintenance of a healthy mitochondrial pool is the removal of dysfunctional organelles via mitophagy. Little is known on how mitophagy is altered with ageing and chronic exercise. We assessed mitophagy flux using colchicine treatment in vivo following chronic contractile activity (CCA) of muscle in young and aged rats. CCA evoked mitochondrial biogenesis in young muscle, with an attenuated response in aged muscle. Mitophagy flux was higher in aged muscle and was correlated with the enhanced expression of mitophagy receptors and upstream transcriptional regulators. CCA decreased mitophagy flux in both age groups, suggesting an improvement in organelle quality. CCA also reduced the exaggerated expression of TFEB evident in aged muscle, which may be promoting the age-induced increase in lysosomal markers. Thus, aged muscle possesses an elevated drive for autophagy and mitophagy which may contribute to the decline in organelle content observed with age, but which may serve to maintain mitochondrial quality. CCA improves organelle integrity and reduces mitophagy, illustrating that chronic exercise is a modality to improve muscle quality in aged populations.

Skeletal muscle is a tissue with a low mitochondrial content under basal conditions, but it is responsive to acute increases in contractile activity patterns (i.e. exercise) which initiate the signalling of a compensatory response, leading to the biogenesis of mitochondria and improved organelle function. Exercise also promotes the degradation of poorly functioning mitochondria (i.e. mitophagy), thereby accelerating mitochondrial turnover, and preserving a pool of healthy organelles. In contrast, muscle disuse, as well as the aging process, are associated with reduced mitochondrial quality and quantity in muscle. This has strong negative implications for whole-body metabolic health and the preservation of muscle mass. A number of traditional, as well as novel regulatory pathways exist in muscle that control both biogenesis and mitophagy. Interestingly, although the ablation of single regulatory transcription factors within these pathways often leads to a reduction in the basal mitochondrial content of muscle, this can invariably be overcome with exercise, signifying that exercise activates a multitude of pathways which can respond to restore mitochondrial health. This knowledge, along with growing realization that pharmacological agents can also promote mitochondrial health independently of exercise, leads to an optimistic outlook in which the maintenance of mitochondrial and whole-body metabolic health can be achieved by taking advantage of the broad benefits of exercise, along with the potential specificity of drug action.

An acute bout of exercise activates downstream signaling cascades that ultimately result in mitochondrial biogenesis. In addition to inducing mitochondrial synthesis, exercise triggers the removal of damaged cellular material via autophagy and of dysfunctional mitochondria through mitophagy. Here, we investigated the necessity of p53 to the changes that transpire within the muscle upon an imposed metabolic and physiological challenge, such as a bout of endurance exercise. We randomly assigned wild-type (WT) and p53 knockout (KO) mice to control, acute exercise (AE; 90 min at 15 m/min), and AE + 3 h recovery (AER) groups and measured downstream alterations in markers of mitochondrial biogenesis, autophagy, and mitophagy. In the absence of p53, activation of p38 MAPK upon exercise was abolished, whereas CaMKII and AMP-activated protein kinase only displayed an attenuated enhancement in the AER group compared with WT mice. The translocation of peroxisome proliferator-activated receptor-γ coactivator-1 α to the nucleus was diminished and only observed in the AER group, and the subsequent increase in messenger RNA transcripts related to mitochondrial biogenesis with exercise and recovery was absent in the p53 KO animals. Whole-muscle autophagic and lysosomal markers did not respond to exercise, irrespective of the genotype of the exercised mice, with the exception of increased ubiquitination observed in KO mice with exercise. Markers of mitophagy were elevated in response to AE and AER conditions in both WT and p53 KO runners. The data suggest that p53 is important for the exercise-induced activation of mitochondrial synthesis and is integral in regulating autophagy during control conditions but not in response to exercise.

-Skeletal muscle undergoes remarkable adaptations in response to chronic decreases in contractile activity, such as a loss of muscle mass, decreases in both mitochondrial content and function, as well as the activation of apoptosis. Although these adaptations are well known, questions remain regarding the signaling pathways that mediated these changes. Autophagy is an organelle turnover pathway that could contribute to these adaptations. The purpose of this study was to determine whether denervation-induced muscle disuse would result in the activation of autophagy gene expression in both wild-type (WT) and Bax/Bak double knockout (DKO) animals, which display an attenuated apoptotic response. Denervation caused a reduction in muscle mass for WT and DKO animals; however, there was a 40% attenuation in muscle atrophy in DKO animals. Mitochondrial state 3 respiration was significantly reduced, and reactive oxygen species production was increased by two-to threefold in both WT and DKO animals. Apoptotic markers, including cytosolic AIF and DNA fragmentation, were elevated in WT, but not in DKO animals following denervation. Autophagy proteins including LC3II, ULK1, ATG7, p62, and Beclin1 were increased similarly following denervation for both WT and DKO. Interestingly, denervation markedly increased the localization of LC3II to subsarcolemmal mitochondria, and this was more pronounced in the DKO animals. Thus denervation-induced muscle disuse activates both apoptotic and autophagic signaling pathways in muscle, and autophagic protein expression does not exhibit a compensatory increase in the presence of attenuated apoptosis. However, the absence of Bax and Bak may represent a potential signal to trigger mitophagy in muscle.reactive oxygen species; muscle atrophy; mitochondria; mitophagy MACROAUTOPHAGY (henceforth referred to as autophagy) is a highly conserved lysosomal-dependent degradation pathway that coordinates and oversees the digestion of organelles, proteins, and intracellular pathogens (4, 34, 42). More than 30 AuTophaGy-related (ATG) regulatory genes products have been identified that are known to facilitate the engulfment of cytoplasmic material into double-membraned vesicles called autophagosomes (4, 42), and to assist in their degradation through fusion with lysosomes (10, 21). As a consequence, autophagy plays a prominent housekeeping role, which maintains homeostasis by selectively eliminating cellular debris. Moreover, although the activity of the autophagic pathway can be increased in response to stress stimuli, the importance of maintaining adequate levels of autophagy for cellular health and function is best demonstrated in several disease conditions, such as Parkinson's and Pompe's disease (27, 41), which are attributable, at least in part, to mutations in either ATG proteins or other autophagy-related genes.Currently there is great interest in determining the meaningful purposes that autophagy has in regulating cellular health, and in more fully understanding the factors that direct selective for...