Secondary Logo

Journal Logo

Mitochondria Initiate and Regulate Sarcopenia

Alway, Stephen E.; Mohamed, Junaith S.; Myers, Matthew J.

Exercise and Sport Sciences Reviews: April 2017 - Volume 45 - Issue 2 - p 58–69
doi: 10.1249/JES.0000000000000101
Perspectives for Progress
Free

We present the hypothesis that an accumulation of dysfunctional mitochondria initiates a signaling cascade leading to motor neuron and muscle fiber death and culminating in sarcopenia. Interactions between neural and muscle cells that contain dysfunctional mitochondria exacerbate sarcopenia. Preventing sarcopenia will require identifying mitochondrial sources of dysfunction that are reversible.

Sarcopenia is characterized by fiber atrophy and loss of fibers. Mitochondria health determines death signaling leading to localized protein loss and, if unchecked, widespread loss of muscle fibers.

1Division of Exercise Physiology; 2Center for Cardiovascular and Respiratory Sciences, and Mitochondria, Metabolism, and Bioenergetics; and 3Centers for Neuroscience, West Virginia University School of Medicine, Morgantown, WV

Address for correspondence: Stephen E. Alway, Ph.D., Division of Exercise Physiology, West Virginia University School of Medicine, 1 Medical Center Dr, Morgantown, PO 9227, WV 26506 (E-mail: salway@hsc.wvu.edu).

Accepted for publication: November 23, 2016.

Editor: Roger M. Enoka, Ph.D.

Key Points

  • Aging-induced mitochondrial insult in muscle and neurons (e.g., oxidative stress, DNA damage, posttranslational modifications) results in mitochondrial permeability transition pore opening.
  • Mitophagy signaling normally removes dysfunctional mitochondria, but this process is impaired in aging muscle cells and motor neurons.
  • Release of the contents from dysfunctional mitochondria to the cytosol initiates local apoptotic signaling that, if left unchecked, activates nuclear fragmentation, cell death, and proteasome activation for cell removal.
  • Cross talk between dysfunctional muscle and motor neuron cells exacerbates the sarcopenic loss of muscle mass and function.
  • To prevent sarcopenia, future studies should identify strategies that reverse mitochondrial modifications to prevent opening of the mitochondrial permeability pore and increase mitophagy in muscle and neuronal cells.
Back to Top | Article Outline

INTRODUCTION

Sarcopenia is associated with increased levels of apoptosis (47) and reduced capabilities for muscle regeneration (41) leading to muscle wasting. For this reason, many studies including our own have focused on the muscle-specific signaling that contributes to muscle wasting in sarcopenia. However, sarcopenia in aged humans and rodents also is associated with motor neuronal death (96,139), which causes impaired innervation (48,106), and a ~27% reduction in the motor unit pool. In aging, a loss of innervation induces profound muscle atrophy (5,106,129). Some denervated fibers become innervated by axons from surviving motor neurons (42,45), whereas other fibers remain denervated and contribute to functional losses in sarcopenia (42).

We postulate that the tight relationship between the loss of motor neurons and muscle cells in aging is explained by a common underlying mechanism that initiates deterioration in these cells. It is interesting that a loss of mitochondria function with aging is a mechanism that is shared by both muscle cells (18,63) and motor neurons (123). Our current perspective and hypothesis is that mitochondrial deterioration in muscles and motor neurons is the primary initiator of sarcopenia (Fig. 1). We have identified some of the data that support this perspective and the areas that are speculative and require additional work to test this hypothesis.

Figure 1

Figure 1

Back to Top | Article Outline

Mitochondrial Regulation of Sarcopenia — Hypothesis

Aging increases mitochondrial stress that sensitizes the opening of the mitochondrial permeability transition pore (mPTP). A loss of mitophagy-proteasome–induced mitochondrial clearance in muscle and motor neuron cells promotes accumulation of poorly functioning mitochondria that have increased mPTP opening. Leakage of the mitochondrial contents to the cell cytosol initiates death (apoptosis) signaling in muscle cells and motor neurons, which contributes to nuclear DNA fragmentation and, if not repaired, nuclear apoptosis. Removal of nuclei in muscle cells and motor neurons leads to fiber and motor neuron death and loss of innervation to the muscle cells. Cross talk between muscles and motor neurons that contain dysfunctional mitochondria exacerbates sarcopenia. Thus, mitochondria are key initiators and regulators of sarcopenia (Fig. 1).

Back to Top | Article Outline

Sources for Mitochondrial Damage in Aging Muscles and Motor Neurons

Our working hypothesis is that sarcopenia is initiated by an aging-associated insult to mitochondria in muscle cells and motor neurons. Mitochondrial stress in aging can originate from greater levels of oxidants, DNA damage, or denervation (31,133).

Back to Top | Article Outline

Reactive Oxygen Species–Induced Damage

Aging increases reactive oxygen species (ROS)–induced production (22) and lowers antioxidant enzyme levels in muscle and neuron cells (58,59,121). ROS production might be secondary to denervation that occurs in muscles from old animals or humans (48,55,133). The accumulation of ROS has the potential to damage cellular mitochondria (reviewed in (15)). The importance of antioxidants in sarcopenia is highlighted by observations that both neural and muscle losses of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) recapitulated sarcopenic muscle loss in a mouse model (125). It is noteworthy that the absence of CuZnSOD in either neural or muscle cells did not manifest full sarcopenic muscle loss (125). However, this observation highlights the need to consider cross talk between these two tissues in aging. Whatever the initial source(s) of ROS production, it is clear that accumulation of excessive ROS contributes to damaged and dysfunctional mitochondria in muscle and neural cells.

Back to Top | Article Outline

Mitochondrial DNA Damage and Aging in Motor Neurons and Muscle Cells

Mitochondrial DNA (mtDNA) deletions or DNA mutations contribute to mitochondrial dysfunction and aging-related muscle fiber loss and atrophy (50,90). In neurons, DNA damage precedes neuronal apoptosis (85), whereas forced repair of DNA damage rescues neurons from elimination by apoptosis (86). Indeed, increased mtDNA mutations have been found in fiber regions that contain oxidative damage (2,90). Furthermore, aging-induced mtDNA deletions are associated closely with a loss of mitochondrial function in motor neurons (123), neuronal malfunction in diseases like Parkinson disease (115), and muscle loss with aging (50,91). Whereas elevated ROS production is not solely the result of mtDNA deletions or mtDNA mutations (141), it is clear that this mechanism contributes to mitochondrial ROS production in aging muscles and neurons (26,86,91).

Back to Top | Article Outline

Mitochondrial Permeability Transition Pore Sensitization with Aging — Mitochondrial Dysfunction

Stress-induced damage to mitochondrial membranes (40,108,144,147) contributes to sensitization of the mitochondrial permeability transition pore (44). The mPTP is a large conductance pore in the inner mitochondrial membrane, which is predominantly closed under nonstressed conditions. Opening of the mPTP can be induced by ROS, increased concentrations of Ca2+, or mitochondrial depolarization. mPTP opening is further exacerbated by an imbalance of Ca2+ homeostasis that likely results from leaky ryanodine receptors in aged skeletal muscle (10). Excessive Ca2+ loading leads to mitochondrial swelling and rupture of the outer mitochondrial membrane.

Opening the mPTP induces a further loss of mitochondrial membrane potential and releases the mitochondrial contents to the cytosol to initiate apoptotic signaling (24,77,89). Apoptosis signaling has been reported in muscle and neuronal cells of aged rodents (4,7,26,34,47,77,88,130) and humans (44,145). Aging-associated muscle denervation also may contribute to increased mPTP opening that in turn induces apoptosis and muscle loss (76,133).

Similar to skeletal muscle cells, ROS damage to mitochondria in neurons from aged animals contributes to mPTP opening (53). This occurs through p66Shc, which generates H2O2 that in turn reacts with cytochrome c and induces oxidation of the mPTP and mitochondrial swelling (126). This mechanism is similar to neural degenerative diseases where induction of ROS (80,113) contributes to motor neuron death (116). Thus, mitochondrial susceptibility to mPTP opening is a common point that triggers downstream cell destruction in both neuron and muscle cells.

Back to Top | Article Outline

Insufficient Mitophagy Allows Unhealthy Mitochondria to Persist in Aging Muscles and Neurons

Damaged mitochondria normally undergo fission, then they are finally removed by mitophagy. However, mitophagy is attenuated with aging in skeletal muscle and motor neurons (40,63,70,127). AMP-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1) trigger the destruction of dysfunctional fragmented mitochondria through FoxO3-dependent autophagy (mitophagy) (94,118). Mitofusin 2 (Mfn2) has an important role regulating mitochondrial fusion, but it also acts as a receptor for Pink1 and Parkin-targeted mitophagy (27). Recent data by Sebastián et al. (127) show that Mfn2 declines in muscle with aging, and loss of Mfn2 produces an aging-like phenotype, including age-associated mitochondrial dysfunction, higher ROS accumulation, and muscle fiber atrophy. Mfn2 also has been implicated in the loss of mitophagy in motor neurons. For example, a reduced inhibition of the E3 ligase Omi/HtrA2 in neuronal mitochondria contributes to a decrease in Mfn2 leading to attenuated mitophagy (29). Thus, an aging-associated deficiency of Mfn2 may be the bridge between impaired mitophagy and an accumulation of dysfunctional mitochondria in muscle and neurons during sarcopenia. However, it should be pointed out that other evidence does not support a decrease in Mfn2 or a decrease in the Mfn2-to-Drp1 ratio that would be expected if Mfn2 were suppressed in muscles of aged mice (75).

Defective mitophagy underlies the progression of motor neuron death in amyotrophic lateral sclerosis (ALS) (38). In contrast, lithium-induced induction of mitophagy (38,101) and mitochondrial biogenesis (101) improve mitochondrial morphology in motor neurons of a G93A SOD-1 mouse model of ALS. Other autophagy proteins, including Pink152, which is the cleavage product of the mitochondrial autophagy protein Pink1, have been implicated in the attenuation of mitophagy in motor neurons. Pink152 can exit the mitochondria in neuron cells and cleave Parkin, which then suppresses its translocation to the mitochondria to attenuate mitophagy (36).

Contrary data suggest that mitophagy may be increased in aging muscles as evidenced by greater migration of Parkin and p62 to the mitochondria (103). Nevertheless, an accumulation of lipofuscin granules suggests a failure of the lysosome to remove dysfunctional mitochondrial in aging even when Parkin has translocated to the mitochondria (103). Indeed, lipofuscin deposits have been reported previously in many tissues including muscles and neurons of aged rodents or other mammals (138). Further work is needed to determine if lysosomal dysfunction (136), loss of Mfn2, or some other protein involved in mitochondrial dynamics regulates mitophagy in sarcopenia.

Back to Top | Article Outline

Local Apoptotic Signaling in Aging Muscles and Motor Neurons Becomes More Widespread to Result in Cell Death

Our hypothetical model to explain the loss of single muscle fibers in sarcopenia is shown in Figure 2. This model assumes that local mitochondrial damage (potentially via ROS, high calcium loads, mtDNA damage, etc.) causes increased mPTP opening, which triggers the contents of the mitochondria to leak to the cytosol. This initiates the intrinsic apoptotic signaling pathway leading to DNA fragmentation and nuclear apoptosis in a localized region of the fiber. An aging suppression of autophagy activators like SIRT1 and Mfn2 or other proteins involved in mitophagy prevents removal of dysfunctional mitochondria via mitophagy and proteasome digestion.

Figure 2

Figure 2

The regional accumulation of damaged mitochondria could extend to other regions within the fiber via their connecting reticular network. As dysfunctional mitochondria accumulate, the region of the fiber that is engulfed by death signaling is expanded. We predict that eventually, the entire fiber would be eliminated, presumably by involving the proteasome. Genes of necrosis also may contribute to the overall cellular removal as sarcopenia progresses (26).

Cardiolipin is an important mitochondria-specific phospholipid, which is concentrated between inner and outer mitochondrial membranes, and redistribution of cardiolipin leads to a localized oligomerization of proapoptotic proteins (83). A local apoptotic cascade could occur via restricted remodeling and redistribution of cardiolipin adjacent to dysfunctional mitochondria. Furthermore, interaction of cardiolipin with the structural protein vimentin (104) could provide a localized cell signaling site for targeted apoptotic disassembly and removal via antivimentin/CL complex antibodies, as has been observed in several pathologies involving apoptosis (104).

Our model for a localized apoptotic and proteolytic signaling cascade that expands to neighboring regions of a muscle fiber (Fig. 2) has strong support from the work of Aiken et al. (26,49,50). For example, Cheema et al. (26) observed a localized aging-induced loss of the mitochondrial enzymes succinate dehydrogenase and cytochrome c oxidase. Interestingly, the same fiber region that had mitochondrial disruption was both atrophic and had high levels of the apoptotic protein caspase-3. In contrast, fiber atrophy and apoptotic signaling did not occur in other regions of the same muscle fibers that were located further away from the dysfunctional mitochondria (26). If the degenerative processes were not initiated locally but rather, from a more general or systemic source, we would expect uniform muscle fiber wasting across its length, but this is not the case. Nevertheless, we predict that the progression of sarcopenia involves a gradual shift from targeted proteins in regions close to dysfunctional mitochondria to a strategy of nontargeted cellular destruction by activating the proteasome pathway when the apoptotic signaling expands to a wider fiber area.

We recognize that mitochondria are represented as distinct organelles in this simplistic model of localized signaling shown in Figure 2. However, mitochondria can range from small individual organelles to rather extensive and connected reticular systems (57). In our model, mitophagy would be expected to target the regional area near dysfunctional mitochondria via the Pink1/Parkin and the LC3-II/autophagy receptor system for lysosomal removal. Although speculative, it is possible that elimination of a section of dysfunctional mitochondria could occur without disruption to the entire network of mitochondria along its reticulum. This could occur by activating fission signaling to wall off a healthy region of the mitochondrial reticulum from a region of dysfunctional mitochondria. Indeed, increased mitochondrial fission dynamics have been reported after muscle denervation (57) and in aging (55,62). On the other hand, insufficient mitophagy in muscles from very old hosts could permit mitochondrial dysfunction in one area to affect other regions along the same mitochondrial reticulum and therefore affect a wider region of the cell.

We speculate that similar to our model in skeletal muscle fibers, motor neurons in aging hosts have increased mPTP opening, leading to apoptotic signaling, but dysfunctional mitochondrial are not removed because mitophagy is suppressed in aging. The apoptotic disassembly of motor neurons could begin regionally near dysfunctional mitochondria and spread to a wider area, resulting in motor neuronal death. Our speculation is supported from data that show that in aging-associated neural diseases, there is a loss of mitochondrial function leading to increased mPTP sensitivity, and attenuated mitophagy that contributes to apoptosis (32,68,86,99,111). Nevertheless, we do not have data to support a process of aging-associated localized motor neuron disassembly outside of neural degenerative disease. Additional work is needed to determine if localized loss of mitochondrial function contributes to a regional concentration of apoptotic signaling in motor neurons in the same way that it might occur in skeletal muscle cells with aging.

Back to Top | Article Outline

Altered Mitochondrial Dynamics With Aging

Abnormal mitochondrial dynamics may negatively affect mitochondrial health. For example, both the mRNA level and the protein abundance of important fusion and fission proteins have been reported to be lower in old as compared with young adult skeletal muscle (55), and this would suggest that the potential for mitochondria to respond to changing environments might be reduced as compared with mitochondria from young hosts. Indeed, this seems to be the case because electron microscopy and biochemical analyses have shown small, more fragmented mitochondria in muscles from old as compared with young adult hosts (56,57), although very large mitochondria also have been noted in muscles from old animals (75). Consistent with the fragmented mitochondrial phenotype in muscles from old hosts, there is evidence to suggest that muscles of aged rodents and humans have a greater overall rate of fission versus fusion (55,62) and lower levels of the fusion protein Opa1 (62) as compared with younger muscles. Fragmented mitochondria tend to have a lower respiratory capacity, and a greater production of ROS, which increases the susceptibility of mitochondria to release its contents and activate the intrinsic caspase apoptotic pathway. Thus, it is not surprising that aging and disuse, which both have excessively fragmented mitochondria, are accompanied by muscle loss (57). It is interesting that a knockout of Mfn 1/2 in skeletal muscle, which prevented mitochondrial fusion, increased the accumulation of mtDNA defects and resulted in muscle atrophy (31). Together, these observations provide support for the idea that muscle mitochondria are important regulators of muscle size. However, to provide a balanced perspective, it is important to point out that other studies have found higher fusion profiles in muscles of humans (14) and prematurely aged mice (63) and larger mitochondria in muscles of old mice (75). It is interesting that studies that have reported a higher fusion index in muscles from old rodents, as indicated by ratios of Mfn1/Mfn2 (63) or Mfn2/Drp1 (75), did not find changes in the protein contents of Mfn1, Mfn2, Opa1, or Drp1. Thus, even when higher fusion indexes are recorded, there still may be more fragmented mitochondria in aged muscles.

The impact of age-associated changes in the mitochondrial dynamics of motor neurons and their potential role in sarcopenia has not been studied. However, dysfunction of mitochondrial dynamics has been reported as an early event in amyotrophic lateral sclerosis (61), which is a common motor neuron disease. Furthermore, increased mitochondrial fragmentation has been found to precede glutamate-induced death of motor neurons (143). Thus, similar to mitochondrial dynamic changes that have been proposed in muscle with aging, motor neuron dysfunction and death may converge on mitochondria, and mitochondrial dynamics may play an important role in regulation of neuronal function that contributes to accelerated sarcopenia.

Back to Top | Article Outline

FOXO Proteins and the UPS in Muscle Atrophy and Sarcopenia

An acceleration of protein turnover with a net loss of protein is downstream of dysfunctional mitochondria, but this represents a major contributor to sarcopenia. AMPK activation (118) and the Forkhead box class O (FOXO) transcription factor family regulate the ubiquitin proteasome system (UPS) and the autophagy-lysosome system. FOXO proteins also regulate the UPS, which is a tightly regulated system responsible for normal intracellular protein turnover and elimination of misfolded and dysfunctional proteins (72,74). FOXOs control the mammalian target of rapamycin complex 1 (MTORC1) signaling, which is associated with muscle hypertrophy (43) and inhibition of mitophagy in skeletal muscle (23). FOXO regulation also occurs by MTORC1-mediated phosphorylation of ULK1 at Ser757 and the subsequent activation of the ULK1-ATG13-RP6KB/ribosomal protein p70S6 kinase in the UPS (23). Inhibition of MTORC1 in muscles of tuberous sclerosis complex knockout mice mimics many features of aging. This includes a loss of muscle mass and strength and attenuated mitophagy (23). However, protein turnover is tightly controlled because MTORC1 is upregulated in denervation-induced muscle atrophy (135). Interestingly, inhibition of MTORC1 reduced muscle atrophy via suppression of E3 ligases, Muscle RING Finger 1 (MuRF-1) and MAFbx/atrogin in response to denervation (135).

FOXO control of the UPS is important in the final steps of degradation of proteins in sarcopenia. FOXOs activate lysosomal cathepsins and cytosolic protease calpains, which progress toward ATP-dependent UPS activation via FOXO3a-associated MuRF-1 and MAFbx regulation (reviewed in (66,117)). Thus, FOXO-mediated autophagy via the UPS may be an important regulator of muscle mass in aging. In future studies, it will be important to determine if failure to regulate FOXO control of MTORC1 or perhaps failure of other proteins that are in the pathways of anabolism might contribute to increased degradation of muscle proteins in aging.

Conflicting data highlight the complexity of understanding the importance of the UPS and atrogenes in sarcopenia. For example, ubiquitin (17), 26S proteasome, polyubiquitinated proteins (3), MuRF-1, and MAFbx expression were all reported to be elevated in hindlimb muscles of sarcopenic rats as compared with young adult animals (3,30). Furthermore, ubiquitin was found to be greater in quadriceps muscles of older (70–79 yr) human subjects as compared with young adults (20–29 yr) (17). In contrast, MuRF-1 and MAFbx expression were reported to be lower in muscles of old rats than young adult rats (35) and not changed with aging in the vastus lateralis of humans (145). The discrepancy between these studies might be due to variability introduced by a low number of subjects or animals in each study and perhaps by some differences in the age and sex of the subjects that were studied. It also is possible that activity, nutritional history, health and smoking habits, etc. will have affected MuRF-1 and MAFbx regulation in these studies. Thus, additional studies are warranted to understand the importance of the UPS in sarcopenia and the role of mitochondria in regulating the UPS more fully.

Back to Top | Article Outline

UPS Disruption Increases Dysfunctional Mitochondria in Muscle and Neural Cells

Aging-associated neural diseases like Parkinson and Alzheimer disease are associated with high ROS levels in neural cells. Reduced mitophagy-associated Pink1- and Parkin-regulated ubiquitination of the outer mitochondrial membrane of damaged mitochondria in aged neurons (79,99,140) contribute to a greater accumulation of ROS (81). High ROS can damage more mitochondria in muscle and neurons (81) and potentially elevate ROS levels even higher. It is therefore likely that proteasome dysfunction contributes to the higher potential for ROS generation in muscles and neuron cells of older individuals or animals.

An association between the UPS and mitochondria occurs through a splice variant of the master mitochondrial regulator peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α2, PGC-1α3, and PGC-1α4 have been shown to stimulate protein synthesis and attenuate UPS activity in cultured myotubes and mouse skeletal muscle (87,119). Furthermore, PGC-1α reduces muscle protein degradation by the UPS via blocking nuclear factor κB and FoxO3 activity (16,124).

Back to Top | Article Outline

Cross Talk Between Mitochondrial Regulators of Autophagy and the UPS

There is considerable communication between the UPS, mitochondrial regulators, and governors of autophagy. For example, silent mating–type information regulation 2 homolog 1 (SIRT1) seems to be part of a pathway that regulates mitophagy. This pathway also involves AMPK, a master energy sensor (20). AMPK increases NAD+ levels, which activates NAD+-dependent SIRT1. Activated SIRT1 deacetylates and activates PCG-1α, which promotes mitochondria synthesis, assembly, growth, and mitochondrial antioxidant production (54). Deacetylation of FOXO1 and FOXO3a by SIRT1 (19,20) mediates autophagic signaling in muscle cells, and aging attenuates SIRT1, which reduces autophagy (134). Furthermore, overexpression of SIRT1 reduces muscle wasting and innervation-induced muscle atrophy by deacetylation and inhibiting FOXO1a and FOXO3, thereby inhibiting induction of MuRF-1 and MAFbx. Future studies should establish the relative importance of cross talk between PGC-1α, FOXO, SIRT1, and the UPS in aging muscles and motor neurons and establish how this affects sarcopenia.

Back to Top | Article Outline

Communication Between Mitochondrial-Induced Death Signaling in Muscle and Motor Neuron Cells Accelerate Cell Death in Aging

Cross talk between muscle and motor neurons is important to both tissues. This has been known for several decades because, when toxins or other compounds are injected into muscles, the compounds undergo retrograde transport to the neuromuscular junction (105), deposit in motor neurons (11), and sometimes contribute to motor neuronal dysfunction (reviewed in (33,39). This communication also is seen when spinal cord injury or denervation induces large-scale muscle wasting (57,76,107,129,131,137), and denervation is a condition often seen as part of sarcopenia. High levels of apoptotic signaling (1,129) and altered autophagy signaling (102,103) with elevated UPS activity (137) occur in muscles after spinal cord injury or denervation. Thus, we would expect that altered neuronal signaling is due at least in part to high ROS production and mitochondrial dysfunction in the muscle cells, and conversely, that neural dysfunction will be communicated to muscle cells (57,100).

The health of muscle cells also affects motor neuron health. For example, increased muscle activity in male G93A SOD1-deficient mice contributes to greater motor impairment and motor neuron–accelerated death (82). This implies that a feedback loop exists that conveys information about muscle activity and the condition of the muscle to the motor neuron. Further evidence of a muscle-to-motor neuron feedback pathway is supported from data showing increases in mitochondrial succinate dehydrogenase activity in motor neurons after functional overload of the plantaris hindlimb muscle in cats (25). Furthermore, the presynaptic motor endplate of the neuromuscular junction is critical for providing retrograde transport to the motor neuron (98).

Observations from aging rats suggest that mitochondria in the axon terminals of the neuromuscular junction undergo swelling, in part from calcium overload. The resulting dysfunction of mitochondrial metabolism and dynamics contributes to elevations in cytosolic cytochrome c and caspase-3 (39). Furthermore, inhibition of synaptic loss reduces apoptosis of motor neurons in a mouse model of motor neuron disease (37). Together, these observations confirm that the same mitochondrial-induced initiation of apoptosis signaling that occurs in skeletal muscle also occurs in neuromuscular junctions with aging. We speculate that in aging, motor neurons receive feedback from deteriorating muscles and neuromuscular junctions, and this communication in turn feeds to a loop of accelerated mitochondrial-induced degenerative changes in motor neurons. Although we cannot rule out the possibility that mitochondrial-induced apoptotic signaling and cell death may occur independently in muscle and motor neuron cells in aging, we have illustrated potential general feedback routes between muscle and motor neuron comparts that may affect the other tissue type, and if this occurs, we would expect sarcopenia to be accelerated (Fig. 1). Clearly, additional studies are needed to test for the presence of these potential communication loops in aging.

Back to Top | Article Outline

Perspectives for Future Progress and the Need for Future Studies

Our hypotheses are based on some speculation, and therefore, additional work is needed to test these hypotheses. Even if the mitochondrial-centered hypothesis for sarcopenia is true, there are unknown factors that would be important to study so that the information can make a practical impact on sarcopenia. A few of these questions are: As mitochondria damage may occur in several different ways (e.g., ubiquination, acetylation, succinylation, ROS damage to inner membrane, mtDNA damage, etc.), which of these (or other pathways) are the most important to sensitize mPTP opening to trigger apoptosis? What is the best strategy to combat mitochondrial dysfunction in aging? If exercise is considered to be a tool for reducing mitochondrial dysfunction, how would exercise target dysfunctional mitochondria? Is it necessary for muscle and neuron cells to improve mitochondria number or just remove dysfunctional mitochondria to slow or prevent sarcopenia? These questions are explored in the following sections, but the lack of clear information emphasizes the need for additional studies to provide these answers.

Back to Top | Article Outline

What Is the Most Important Source of Mitochondrial Damage that Triggers Apoptosis and Cell Death?

We have focused on ROS damage to the inner mitochondrial membrane (15,21,22,79) and mtDNA damage (22,26,50,63,73) as two important ways that might impair mitochondrial function in aging muscles and motor neurons. However, mitochondrial damage and modifications also may occur by posttranslational modifications such as ubiquitination (67,99,140,148), acetylation (9,21,28), succinylation (114,150), and phosphorylation (51,73,79). Other potential sources of mitochondrial damage include excessive calcium loading (9,28). Likely, some damage is repairable, whereas other damage contributes to irreparable mPTP opening leading to nuclear apoptosis and cell death. It is important to identify which of these (or other pathways) provide potential reversible mitochondrial damage and which cause irreversible damage that promotes apoptosis.

Back to Top | Article Outline

Potential Strategies Using Exercise and Nutrition to Reduce Sarcopenia Should Focus on Mitochondrial Health

Exercise interventions and nutritional manipulations have produced some successes for reducing although not fully eliminating sarcopenia. A logical place to begin the search for ways by which exercise and nutritional approaches might better attenuate sarcopenia is by targeting these strategies to maximize mitochondrial health. This includes identifying the mitochondrial modifications that are reversible by exercise and nutritional interventions in aging. For example, mitochondrial acetylation is reversible at least under some circumstances including exercise (97). Proteins like SIRT1 and SIRT3 may be important regulators of deacetylation in mitochondria (46,97,132). SIRT1 is important for deacetylation of mitochondrial-interacting targets like PGC-1α, FOXO3, p53, and NF-kB (reviewed in (13,110) and has been implicated in improving function and life span in aging (95). Furthermore, SIRT1 deacetylation of Mfn2 may be important for regulating mitophagy and removing dysfunctional mitochondria (132). In addition, evidence from nonmuscle and nonneuronal cells suggests that mPTP-mediated pore opening and apoptosis can be inhibited by deacetylation of mitochondria by SIRT3 (46).

Exercise training and nutrition could be used as an intervention to increase SIRT1 and SIRT3 activity with the goal of increasing mitophagy and mitochondrial biogenesis pathways in muscle and neuronal cells. However, aging is associated with high cell levels of ROS, and ROS accumulation is an inductor for mPTP opening. ROS accumulation could increase with exercise, and this may be why exercise has only been partially successful in reducing sarcopenia. We postulate that nutritional regulation of oxidants should be considered to minimize the additional ROS burden (58,59,120–122) when initiating exercise training in the elderly to minimize mPTP opening. Future studies could test if nutritional antioxidants would minimize excessive ROS accumulation, oxidant damage, and mPTP opening in muscles and neurons when elderly persons begin an exercise program. If this were the case, we would predict that antioxidant supplements should be slowly reduced after some duration of training adaption has passed to permit cellular increases in SIRT1/SIRT3 and antioxidant defenses for the elderly subjects without risking excessive ROS damage.

Back to Top | Article Outline

How Might Exercise Target Dysfunctional Mitochondria by Mitophagy?

Studies in rodents have shown an increased abundance of autophagy proteins including Drp1 and Bcl-2 and 19 kDa interacting protein-3 (Bnip3) after exercise (60,65,71,78). Bnip3 functions as a mitophagy receptor to recruit selected autophagosomes for elimination. Exercise-induced Pink1 activation of Drp1 (112) also could target dysfunctional mitochondria for mitophagy. This idea is supported by recent data from Mejias-Pena et al. (92), who found an increase in the protein abundance of autophagy proteins Beclin-1, Atg12, Atg16, and the LC3II/I ratio in blood mononuclear cells of elderly subjects after 8 wk of aerobic exercise. Furthermore, 8 wk of aerobic exercise has been reported to increase autophagy proteins Beclin-1, ATG7, and MuRF-1 in muscles of old mice (70). Indeed, it has been proposed that autophagy signals are necessary to achieve aerobic improvements in skeletal muscle (78). Thus, autophagy proteins may be important for an exercise-mediated slowing of sarcopenia. If the same processes occur in humans as is the case in rodents and nonhuman mammals (64), exercise, or nutritional intervention such as caloric restriction, also would be expected to increase mitophagy removal of dysfunctional mitochondria, so the mitochondria that remain are proportionally healthier (64).

Although clearly speculative, we postulate that, in response to exercise or nutritional interventions, mitochondria that are the most dysfunctional would provide the greatest magnitude of apoptotic signaling and be more likely to attract autophagy linker proteins (e.g., p62) for elimination by mitophagy. Future studies are needed to identify the precise signatures of local death signaling around individual dysfunctional mitochondria and to determine which autophagy receptors are reduced by exercise or nutritional interventions and to examine if activated LC3-II is attenuated or eliminated once dysfunctional mitochondria are removed. This will take technology that is able to identify dysfunctional from healthy mitochondria and sample the milieu adjacent to each mitochondria.

Although speculative, exercise or nutritional modifications might target dysfunctional mitochondria for elimination via an autophagy pathway called chaperone-mediated autophagy (CMA). CMA involves the binding of constitutive heat shock 70 to selected proteins, which are targeted to the lysosomal membrane where they interact with membrane receptor lysosomal-associated membrane protein 2A (LAMP2A). Aging causes degradation and availability of LAMP2A in the lysosomal membranes (69), which reduces the effectiveness of CMA. Future studies should evaluate the role of LAMP2A and determine if exercise or nutritional interventions increase CMA and target dysfunctional mitochondria for mitophagy in muscles and motor neurons of old animals or humans.

Another potential way that exercise could selectively target dysfunctional mitochondria is through elevation of Parkin or the degradation of PARK7/DJ-1 (142). PARK7 is an antioxidant protein that limits mitochondrial damage in response to oxidative stress (12), and it regulates skeletal muscle contractile protein synthesis and hypertrophy (149). Overexpression of PARK7 reduces mitochondrial dysfunction under oxidative stress (142), which shows a direct link between autophagy and mitochondrial function. Future studies should identify if exercise or nutritional intervention (e.g., antioxidants, caloric restriction) improves PARK7 expression in muscles and motor neurons of old hosts, and if the change in PARK7 directly mediates improvements in mitochondrial function of skeletal muscle.

Parkin and Pink1 are attractive candidates for targeting dysfunctional mitochondria, which we speculate would occur in response to exercise. This is because accumulation of Pink1 at the outer mitochondrial membrane provides a precise mechanism to identify dysfunctional mitochondria from healthy ones. Pink1 promotes Parkin recruitment to activate mitophagy and UPS signaling. However, overexpression of PGC-1α was reported to attenuate Pink1 levels in response to remobilization of muscle (67). As we would expect exercise to increase mitochondrial biogenesis through the PGC-1α axis, it is not known if Pink1 plays an important role in an exercise-mediated increase in mitophagy of muscle cells and motor neurons of aged humans or rodents.

Back to Top | Article Outline

The Potential Role for Mitochondrial Biogenesis to Reduce Sarcopenia

In addition to increasing mitophagy, exercise and nutritional interventions might be expected to increase mitochondrial biogenesis and, therefore, replace the dysfunctional mitochondria that are removed by mitophagy. Both endurance and resistance exercise have been associated with elevated mitochondrial biogenesis (93,109). Relative mitochondrial activity corresponds with fractional protein synthesis rates because many proteins complete their translation at mitochondria (84). There is an assumption that endurance and strength training by older adults induces mitochondrial biogenesis, but given the propensity for mtDNA damage and high ROS levels in aging, this remains uncertain. If newly synthesized mitochondria were generated in exercised muscles and motor neurons from aged hosts, but the new mitochondrial were unhealthy (e.g., incompletely folded proteins), the mitophagy signals (from exercise or nutritional interventions) would need to be even higher to remove these newly formed but dysfunctional mitochondria. Clearly, additional work is needed before we fully understand if exercise or nutritional interventions synthesize completely functional and healthy mitochondria in aged hosts, or if the basal environment of oxidative stress, etc. results in a new population of unhealthy mitochondria that also must be targeted for mitophagic removal in the elderly.

We know that exercise downregulates apoptosis and upregulates mitophagy (4,52,128,146). Nevertheless, future studies should explore the mechanisms by which exercise activates mitophagic, and attenuates apoptotic and necrotic, signaling pathways in muscle cells and motor neurons of older individuals (4,47). We recognize that increased apoptosis and reduced mitophagy have not been identified as an aging-related condition in every study, but in our view, there are sufficient data to suggest that this is probably an underlying process for most cells in aging. Nevertheless, some of the mitochondrial mediated pathways leading to motor neuron death in aging have not received much attention and should be the investigation of future work.

Future experiments also should identify novel proteins and protein functions that better define the communication of dysfunctional signaling between motor neurons and muscle cells in aging. Modern genetic approaches, including RNA-seq and proteome pathway analysis, will likely be required. It also will be important to find out if it is possible to reverse the process responsible for regional disassembly in the absence of mitochondrial biogenesis and then to focus on molecular events and targets in muscle and motor neurons that are upstream of this point. In the quest to attenuate sarcopenia, it also will be important to understand the limit for mitochondrial health to impact satellite cell function for repairing and replacing sections of fibers or whole fibers because satellite cells are affected adversely by aging, mitochondrial damage, and death signaling (4,6,7,144).

Back to Top | Article Outline

CONCLUSIONS

Mitochondrial-regulated apoptosis provides a strong signaling network that contributes to sarcopenia (8). We have taken the perspective that both neural and muscle components contribute to muscle wasting, but mitochondrial health is central to initiating and perpetuating the signal for sarcopenia. We argue that mitochondrial dysfunction leads to increased mPTP opening and initiates apoptotic signaling in muscle cells and motor neurons. In aging, this is not corrected because mitophagy is inhibited. Proteasome activation leads to removal of cellular contents close to the site of dysfunctional mitochondria, and this cellular dismantling expands proportionally to the accumulation of dysfunctional mitochondria. Although aging induces widespread systemic mitochondrial dysfunction, perhaps as a result of high ROS or accumulation of mtDNA damage, we have considered that retrograde and anterograde communication likely exists between dying muscle and motor neurons, which may accelerate death in both compartments.

Additional studies are needed to establish if exercise and nutrition can be used to effectively improve mitochondria health and reduce sarcopenia in aging populations. In our view, targeting dysfunctional mitochondria and increasing healthy mitochondria in motor neurons and muscle fibers provide the best strategy for reducing sarcopenia.

Back to Top | Article Outline

Acknowledgments

The authors acknowledge the facilities and staff of the West Virginia University Microscope Imaging Facility, which is supported by the Mary Babb Randolph Cancer Center and NIH grant 5P20RR016440, P30RR032138/GM103488, and P20RR016477.

This study was supported by the National Institute of General Medical Sciences, U54GM104942 U54GM104942, the Genomics Core Facility and WV-INBRE (NIH grant P20GM103434), and a grant from WV Program to Stimulate Competitive Research (PSCoR) to SEA.

Back to Top | Article Outline

References

1. Adhihetty PJ, O'Leary MF, Chabi B, Wicks KL, Hood DA. Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle. J. Appl. Physiol. 2007; 102:1143–51.
2. Aiken J, Bua E, Cao Z, et al. Mitochondrial DNA deletion mutations and sarcopenia. Ann. N. Y. Acad. Sci. 2002; 959:412–23.
3. Altun M, Besche HC, Overkleeft HS, et al. Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway. J. Biol. Chem. 2010; 285:39597–608.
4. Alway SE, Bennett BT, Wilson JC, et al. Green tea extract attenuates muscle loss and improves muscle function during disuse, but fails to improve muscle recovery following unloading in aged rats. J. Appl. Physiol. 2015; 118:319–30.
5. Alway SE, Degens H, Krishnamurthy G, Chaudhrai A. Denervation stimulates apoptosis but not Id2 expression in hindlimb muscles of aged rats. J. Gerontol. A. Biol. Sci. Med. Sci. 2003; 58:687–97.
6. Alway SE, Myers MJ, Mohamed JS. Regulation of satellite cell function in sarcopenia. Front. Aging Neurosci. 2014; 6:246.
7. Alway SE, Pereira SL, Edens NK, Hao Y, Bennett BT. β-Hydroxy-β-methylbutyrate (HMB) enhances the proliferation of satellite cells in fast muscles of aged rats during recovery from disuse atrophy. Exp. Gerontol. 2013; 48:973–84.
8. Alway SE, Siu PM. Nuclear apoptosis contributes to sarcopenia. Exerc. Sport Sci. Rev. 2008; 36:51–7.
9. Amigo I, Menezes-Filho SL, Luévano-Martínez LA, Chausse B, Kowaltowski AJ. Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity. Aging Cell. 2017; 16:73–81.
10. Andersson DC, Betzenhauser MJ, Reiken S, et al. Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metab. 2011; 14:196–207.
11. Arvidson B. Inorganic mercury is transported from muscular nerve terminals to spinal and brainstem motoneurons. Muscle Nerve. 1992; 15:1089–94.
12. Billia F, Hauck L, Grothe D, et al. Parkinson-susceptibility gene DJ-1/PARK7 protects the murine heart from oxidative damage in vivo. Proc. Natl. Acad. Sci. U. S. A. 2013; 110:6085–90.
13. Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell. Biol. 2016; 17:679–90.
14. Bori Z, Zhao Z, Koltai E, et al. The effects of aging, physical training, and a single bout of exercise on mitochondrial protein expression in human skeletal muscle. Exp. Gerontol. 2012; 47:417–24.
15. Brand MD. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic. Biol. Med. 2016; 100:14–31.
16. Brault JJ, Jespersen JG, Goldberg AL. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J. Biol. Chem. 2010; 285:19460–71.
17. Cai D, Lee KK, Li M, Tang MK, Chan KM. Ubiquitin expression is up-regulated in human and rat skeletal muscles during aging. Arch. Biochem. Biophys. 2004; 425:42–50.
18. Calvani R, Joseph AM, Adhihetty PJ, et al. Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy. Biol. Chem. 2013; 394:393–414.
19. Canto C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature. 2009; 458:1056–60.
20. Canto C, Jiang LQ, Deshmukh AS, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell. Metab. 2010; 11:213–9.
21. Capitanio D, Vasso M, De PS, et al. Specific protein changes contribute to the differential muscle mass loss during ageing. Proteomics. 2016; 16:645–56.
22. Carter HN, Chen CC, Hood DA. Mitochondria, muscle health, and exercise with advancing age. Physiology (Bethesda). 2015; 30:208–23.
23. Castets P, Ruegg MA. MTORC1 determines autophagy through ULK1 regulation in skeletal muscle. Autophagy. 2013; 9:1435–7.
24. Chabi B, Ljubicic V, Menzies KJ, Huang JH, Saleem A, Hood DA. Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging Cell. 2008; 7:2–12.
25. Chalmers GR, Roy RR, Edgerton VR. Motoneuron and muscle fiber succinate dehydrogenase activity in control and overloaded plantaris. J. Appl. Physiol. 1991; 71:1589–92.
26. Cheema N, Herbst A, McKenzie D, Aiken JM. Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities. Aging Cell. 2015; 14:1085–93.
27. Chen Y, Dorn GW. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. 2013; 340:471–5.
28. Cheng A, Yang Y, Zhou Y, et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell. Metab. 2016; 23:128–42.
29. Cilenti L, Ambivero CT, Ward N, Alnemri ES, Germain D, Zervos AS. Inactivation of Omi/HtrA2 protease leads to the deregulation of mitochondrial Mulan E3 ubiquitin ligase and increased mitophagy. Biochim. Biophys. Acta. 2014; 1843:1295–307.
30. Clavel S, Coldefy AS, Kurkdjian E, Salles J, Margaritis I, Derijard B. Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat tibialis anterior muscle. Mech. Ageing Dev. 2006; 127:794–801.
31. Correia-Melo C, Marques FD, Anderson R, et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 2016; 35:724–42.
32. Dabrowska A, Venero JL, Iwasawa R, et al. PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity. Aging (Albany NY). 2015; 7:629–47.
33. Deinhardt K, Schiavo G. Endocytosis and retrograde axonal traffic in motor neurons. Biochem. Soc. Symp. 2005:139–150.
34. Dirks A, Leeuwenburgh C. Apoptosis in skeletal muscle with aging. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2002; 282:R519–27.
35. Edstrom E, Altun M, Hagglund M, Ulfhake B. Atrogin-1/MAFbx and MuRF1 are downregulated in aging-related loss of skeletal muscle. J. Gerontol. A. Biol. Sci. Med. Sci. 2006; 61:663–74.
36. Fedorowicz MA, de Vries-Schneider RL, Rub C, et al. Cytosolic cleaved PINK1 represses Parkin translocation to mitochondria and mitophagy. EMBO Rep. 2014; 15:86–93.
37. Ferri A, Sanes JR, Coleman MP, Cunningham JM, Kato AC. Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr. Biol. 2003; 13:669–73.
38. Fornai F, Longone P, Ferrucci M, et al. Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy. 2008; 4:527–30.
39. García ML, Fernández A, Solas MT. Mitochondria, motor neurons and aging. J. Neurol. Sci. 2013; 330:18–26.
40. García-Prat L, Martínez-Vicente M, Perdiguero E, et al. Autophagy maintains stemness by preventing senescence. Nature. 2016; 529:37–42.
41. García-Prat L, Sousa-Victor P, Munoz-Canoves P. Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells. FEBS J. 2013; 280:4051–62.
42. Gilmore KJ, Morat T, Doherty TJ, Rice CL. Motor unit number estimations and neuromuscular fidelity in three stages of sarcopenia. Muscle Nerve. 2016. Epub ahead of print.
43. Goodman CA, Frey JW, Mabrey DM, et al. The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth. J. Physiol. 2011; 589:5485–501.
44. Gouspillou G, Sgarioto N, Kapchinsky S, et al. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 2014; 28:1621–33.
45. Gutmann E, Hanzlikova V. Denervation, reinnervation and regeneration of senile muscle. Adv. Exp. Med. Biol. 1975; 53:431–40.
46. Hafner AV, Dai J, Gomes AP, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY). 2010; 2:914–23.
47. Hao Y, Jackson JR, Wang Y, Edens N, Pereira SL, Alway SE. β-Hydroxy-β-methylbutyrate reduces myonuclear apoptosis during recovery from hind limb suspension-induced muscle fiber atrophy in aged rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2011; 301:R701–15.
48. Hepple RT, Rice CL. Innervation and neuromuscular control in ageing skeletal muscle. J. Physiol. 2016; 594:1965–78.
49. Herbst A, Pak JW, McKenzie D, Bua E, Bassiouni M, Aiken JM. Accumulation of mitochondrial DNA deletion mutations in aged muscle fibers: evidence for a causal role in muscle fiber loss. J. Gerontol. A. Biol. Sci. Med. Sci. 2007; 62:235–45.
50. Herbst A, Wanagat J, Cheema N, Widjaja K, McKenzie D, Aiken JM. Latent mitochondrial DNA deletion mutations drive muscle fiber loss at old age. Aging Cell. 2016. Epub ahead of print.
51. Hofer A, Wenz T. Post-translational modification of mitochondria as a novel mode of regulation. Exp. Gerontol. 2014; 56:202–20.
52. Hood DA. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Appl. Physiol. Nutr. Metab. 2009; 34:465–72.
53. Hou Y, Ghosh P, Wan R, et al. Permeability transition pore-mediated mitochondrial superoxide flashes mediate an early inhibitory effect of amyloid beta1-42 on neural progenitor cell proliferation. Neurobiol. Aging. 2014; 35:975–89.
54. Hsu CP, Odewale I, Alcendor RR, Sadoshima J. Sirt1 protects the heart from aging and stress. Biol. Chem. 2008; 389:221–31.
55. Ibebunjo C, Chick JM, Kendall T, et al. Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia. Mol. Cell. Biol. 2013; 33:194–212.
56. Iqbal S, Hood DA. The role of mitochondrial fusion and fission in skeletal muscle function and dysfunction. Front. Biosci. (Landmark Ed.). 2015; 20:157–72.
57. Iqbal S, Ostojic O, Singh K, Joseph AM, Hood DA. Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse. Muscle Nerve. 2013; 48:963–70.
58. Jackson JR, Ryan MJ, Alway SE. Long-term supplementation with resveratrol alleviates oxidative stress but does not attenuate sarcopenia in aged mice. J. Gerontol. A. Biol. Sci. Med. Sci. 2011; 66:751–64.
59. Jackson JR, Ryan MJ, Hao Y, Alway SE. Mediation of endogenous antioxidant enzymes and apoptotic signaling by resveratrol following muscle disuse in the gastrocnemius muscles of young and old rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010; 299:R1572–81.
60. Jamart C, Naslain D, Gilson H, Francaux M. Higher activation of autophagy in skeletal muscle of mice during endurance exercise in the fasted state. Am. J. Physiol. Endocrinol. Metab. 2013; 305:E964–74.
61. Jiang Z, Wang W, Perry G, Zhu X, Wang X. Mitochondrial dynamic abnormalities in amyotrophic lateral sclerosis. Transl. Neurodegener. 2015; 4:14.
62. Joseph AM, Adhihetty PJ, Buford TW, et al. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell. 2012; 11:801–9.
63. Joseph AM, Adhihetty PJ, Wawrzyniak NR, et al. Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. PLoS One. 2013; 8:e69327.
64. Joseph AM, Malamo AG, Silvestre J, et al. Short-term caloric restriction, resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber-type specific manner in aged animals. Exp. Gerontol. 2013; 48:858–68.
65. Ju JS, Jeon SI, Park JY, et al. Autophagy plays a role in skeletal muscle mitochondrial biogenesis in an endurance exercise-trained condition. J. Physiol. Sci. 2016; 66:417–30.
66. Kandarian SC, Jackman RW. Intracellular signaling during skeletal muscle atrophy. Muscle Nerve. 2006; 33:155–65.
67. Kang C, Ji LL. PGC-1α overexpression via local transfection attenuates mitophagy pathway in muscle disuse atrophy. Free Radic. Biol. Med. 2016; 93:32–40.
68. Kang S, Fernandes-Alnemri T, Alnemri ES. A novel role for the mitochondrial HTRA2/OMI protease in aging. Autophagy. 2013; 9:420–1.
69. Kiffin R, Kaushik S, Zeng M, et al. Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J. Cell. Sci. 2007; 120:782–91.
70. Kim YA, Kim YS, Oh SL, Kim HJ, Song W. Autophagic response to exercise training in skeletal muscle with age. J. Physiol. Biochem. 2013; 69:697–705.
71. Kitaoka Y, Ogasawara R, Tamura Y, Fujita S, Hatta H. Effect of electrical stimulation-induced resistance exercise on mitochondrial fission and fusion proteins in rat skeletal muscle. Appl. Physiol. Nutr. Metab. 2015; 40:1137–42.
72. Koga H, Kaushik S, Cuervo AM. Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res. Rev. 2011; 10:205–15.
73. Latorre-Pellicer A, Moreno-Loshuertos R, Lechuga-Vieco AV, et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature. 2016; 535:561–5.
74. Lecker SH, Jagoe RT, Gilbert A, et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 2004; 18:39–51.
75. Leduc-Gaudet JP, Picard M, St-Jean PF, et al. Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. Oncotarget. 2015; 6:17923–37.
76. Lee G, Lim JY, Frontera WR. Apoptosis in young and old denervated rat skeletal muscle. Muscle Nerve. 2016. Epub ahead of print.
77. Leeuwenburgh C, Gurley CM, Strotman BA, Dupont-Versteegden EE. Age-related differences in apoptosis with disuse atrophy in soleus muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005; 288:R1288–96.
78. Lira VA, Okutsu M, Zhang M, et al. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J. 2013; 27:4184–93.
79. Liu W, Acin-Perez R, Geghman KD, Manfredi G, Lu B, Li C. Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission. Proc. Natl. Acad. Sci. U. S. A. 2011; 108:12920–4.
80. Liu X, Xu S, Wang P, Wang W. Transient mitochondrial permeability transition mediates excitotoxicity in glutamate-sensitive NSC34D motor neuron-like cells. Exp. Neurol. 2015; 271:122–30.
81. Maharjan S, Oku M, Tsuda M, Hoseki J, Sakai Y. Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition. Sci. Rep. 2014; 4:5896.
82. Mahoney DJ, Rodriguez C, Devries M, Yasuda N, Tarnopolsky MA. Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis. Muscle Nerve. 2004; 29:656–62.
83. Manganelli V, Capozzi A, Recalchi S, et al. Altered traffic of cardiolipin during apoptosis: exposure on the cell surface as a trigger for "antiphospholipid antibodies". J. Immunol. Res. 2015; 2015:847985.
84. Margeot A, Garcia M, Wang W, Tetaud E, di Rago JP, Jacq C. Why are many mRNAs translated to the vicinity of mitochondria: a role in protein complex assembly? Gene. 2005; 354:64–71.
85. Martin LJ, Liu Z. Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent. J. Neurobiol. 2002; 50:181–97.
86. Martin LJ, Wong M. Enforced DNA repair enzymes rescue neurons from apoptosis induced by target deprivation and axotomy in mouse models of neurodegeneration. Mech. Ageing Dev. 2016. Epub ahead of print.
87. Martínez-Redondo V, Jannig PR, Correia JC, et al. Peroxisome proliferator-activated receptor γ coactivator-1 α isoforms selectively regulate multiple splicing events on target genes. J. Biol. Chem. 2016; 291:15169–84.
88. Marzetti E, Carter CS, Wohlgemuth SE, et al. Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction. Mech. Ageing Dev. 2009; 130:272–80.
89. Marzetti E, Wohlgemuth SE, Lees HA, Chung HY, Giovannini S, Leeuwenburgh C. Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle. Mech. Ageing Dev. 2008; 129:542–9.
90. McKenzie D, Bua E, McKiernan S, Cao Z, Aiken JM. Mitochondrial DNA deletion mutations: a causal role in sarcopenia. Eur. J. Biochem. 2002; 269:2010–5.
91. McKiernan SH, Colman R, Lopez M, Beasley TM, Weindruch R, Aiken JM. Longitudinal analysis of early stage sarcopenia in aging rhesus monkeys. Exp. Gerontol. 2009; 44:170–6.
92. Mejías-Peña Y, Rodriguez-Miguelez P, Fernandez-Gonzalo R, et al. Effects of aerobic training on markers of autophagy in the elderly. Age (Dordr). 2016; 38:33.
93. Menzies KJ, Singh K, Saleem A, Hood DA. Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis. J. Biol. Chem. 2013; 288:6968–79.
94. Milan G, Romanello V, Pescatore F, et al. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat. Commun. 2015; 6:6670.
95. Mitchell SJ, Martin-Montalvo A, Mercken EM, et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell. Rep. 2014; 6:836–43.
96. Mittal KR, Logmani FH. Age-related reduction in 8th cervical ventral nerve root myelinated fiber diameters and numbers in man. J. Gerontol. 1987; 42:8–10.
97. Mohamed JS, Wilson JC, Myers MJ, Sisson KJ, Alway SE. Dysregulation of SIRT-1 in aging mice increases skeletal muscle fatigue by a PARP-1-dependent mechanism. Aging (Albany NY). 2014; 6:820–34.
98. Mohan R, Tosolini AP, Morris R. Targeting the motor end plates in the mouse hindlimb gives access to a greater number of spinal cord motor neurons: an approach to maximize retrograde transport. Neuroscience. 2014; 274:318–30.
99. Moussa CE. Parkin is dispensable for mitochondrial function, but its ubiquitin ligase activity is critical for macroautophagy and neurotransmitters: therapeutic potential beyond Parkinson's disease. Neurodegener. Dis. 2015; 15:259–70.
100. Muller FL, Song W, Jang YC, et al. Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007; 293:R1159–68.
101. Natale G, Lenzi P, Lazzeri G, et al. Compartment-dependent mitochondrial alterations in experimental ALS, the effects of mitophagy and mitochondriogenesis. Front Cell Neurosci. 2015; 9:434.
102. O'Leary MF, Vainshtein A, Carter HN, Zhang Y, Hood DA. Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals. Am. J. Physiol. Cell. Physiol. 2012; 303:C447–54.
103. O'Leary MF, Vainshtein A, Iqbal S, Ostojic O, Hood DA. Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle. Am. J. Physiol. Cell. Physiol. 2013; 304:C422–30.
104. Ortona E, Capozzi A, Colasanti T, et al. Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome. Blood. 2010; 116:2960–7.
105. Pamphlett R, Bayliss A. Lead uptake in motor axons. Muscle Nerve. 1992; 15:620–5.
106. Pannerec A, Springer M, Migliavacca E, et al. A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia. Aging (Albany NY). 2016; 8:712–29.
107. Pelletier CA, Miyatani M, Giangregorio L, Craven BC. Sarcopenic obesity in adults with spinal cord injury: a cross-sectional study. Arch. Phys. Med. Rehabil. 2016; 97:1931–7.
108. Porter C, Hurren NM, Cotter MV, et al. Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2015; 309:E224–32.
109. Porter C, Reidy PT, Bhattarai N, Sidossis LS, Rasmussen BB. Resistance exercise training alters mitochondrial function in human skeletal muscle. Med. Sci. Sports Exerc. 2015; 47:1922–31.
110. Poulose N, Raju R. Sirtuin regulation in aging and injury. Biochim. Biophys. Acta. 2015; 1852:2442–55.
111. Precht TA, Phelps RA, Linseman DA, et al. The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis. Cell. Death Differ. 2005; 12:255–65.
112. Pryde KR, Smith HL, Chau KY, Schapira AH. PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J. Cell. Biol. 2016; 213:163–71.
113. Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fischbeck KH. Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum. Mol. Genet. 2009; 18:27–42.
114. Rardin MJ, He W, Nishida Y, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell. Metab. 2013; 18:920–33.
115. Reeve A, Meagher M, Lax N, et al. The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons. J. Neurosci. 2013; 33:10790–801.
116. Rojas F, Gonzalez D, Cortes N, et al. Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of ALS through activation of c-Abl signaling. Front. Cell. Neurosci. 2015; 9:203.
117. Rom O, Reznick AZ. The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass. Free Radic. Biol. Med. 2016; 98:218–30.
118. Romanello V, Guadagnin E, Gomes L, et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 2010; 29:1774–85.
119. Ruas JL, White JP, Rao RR, et al. A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell. 2012; 151:1319–31.
120. Ryan MJ, Dudash HJ, Docherty M, et al. Aging-dependent regulation of antioxidant enzymes and redox status in chronically loaded rat dorsiflexor muscles. J. Gerontol. A. Biol. Sci. Med. Sci. 2008; 63:1015–26.
121. Ryan MJ, Jackson JR, Hao Y, Leonard SS, Alway SE. Inhibition of xanthine oxidase reduces oxidative stress and improves skeletal muscle function in response to electrically stimulated isometric contractions in aged mice. Free Radic. Biol. Med. 2011; 51:38–52.
122. Ryan MJ, Jackson JR, Hao Y, et al. Suppression of oxidative stress by resveratrol after isometric contractions in gastrocnemius muscles of aged mice. J. Gerontol. A. Biol. Sci. Med. Sci. 2010; 65:815–31.
123. Rygiel KA, Grady JP, Turnbull DM. Respiratory chain deficiency in aged spinal motor neurons. Neurobiol. Aging. 2014; 35:2230–8.
124. Sandri M, Lin J, Handschin C, et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl. Acad. Sci. U. S. A. 2006; 103:16260–5.
125. Sataranatarajan K, Qaisar R, Davis C, et al. Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype. Redox. Biol. 2015; 5:140–8.
126. Savino C, Pelicci P, Giorgio M. The P66Shc/mitochondrial permeability transition pore pathway determines neurodegeneration. Oxid. Med. Cell. Longev. 2013; 2013:719407.
127. Sebastian D, Sorianello E, Segales J, et al. Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway. EMBO J. 2016; 35:1677–93.
128. Sin TK, Yu AP, Yung BY, et al. Effects of long-term resveratrol-induced SIRT1 activation on insulin and apoptotic signalling in aged skeletal muscle. Acta Diabetol. 2015; 52:1063–75.
129. Siu PM, Alway SE. Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle. J. Physiol. 2005; 565:309–23.
130. Siu PM, Alway SE. Aging alters the reduction of pro-apoptotic signaling in response to loading-induced hypertrophy. Exp. Gerontol. 2006; 41:175–88.
131. Siu PM, Alway SE. Deficiency of the Bax gene attenuates denervation-induced apoptosis. Apoptosis. 2006; 11:967–81.
132. Sooyeon L, Go KL, Kim JS. Deacetylation of mitofusin-2 by sirtuin-1: a critical event in cell survival after ischemia. Mol. Cell. Oncol. 2015; 3:e1087452.
133. Spendiff S, Vuda M, Gouspillou G, et al. Denervation drives mitochondrial dysfunction in skeletal muscle of octogenarians. J. Physiol. 2016; 594:7361–79.
134. Tang AH, Rando TA. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 2014; 33:2782–97.
135. Tang H, Inoki K, Lee M, et al. mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases. Sci. Signal. 2014; 7:ra18.
136. Terman A, Kurz T, Gustafsson B, Brunk UT. The involvement of lysosomes in myocardial aging and disease. Curr. Cardiol. Rev. 2008; 4:107–15.
137. Thakore NP, Samantaray S, Park S, et al. Molecular changes in sub-lesional muscle following acute phase of spinal cord injury. Neurochem. Res. 2016; 41:44–52.
138. Tohma H, Hepworth AR, Shavlakadze T, Grounds MD, Arthur PG. Quantification of ceroid and lipofuscin in skeletal muscle. J. Histochem. Cytochem. 2011; 59:769–79.
139. Tomlinson BE, Irving D. The numbers of limb motor neurons in the human lumbosacral cord throughout life. J. Neurol. Sci. 1977; 34:213–9.
140. Triplett JC, Zhang Z, Sultana R, et al. Quantitative expression proteomics and phosphoproteomics profile of brain from PINK1 knockout mice: insights into mechanisms of familial Parkinson's disease. J. Neurochem. 2015; 133:750–65.
141. Wanagat J, Ahmadieh N, Bielas JH, Ericson NG, Van Remmen H. Skeletal muscle mitochondrial DNA deletions are not increased in CuZn-superoxide dismutase deficient mice. Exp. Gerontol. 2015; 61:15–9.
142. Wang B, Cai Z, Tao K, et al. Essential control of mitochondrial morphology and function by chaperone-mediated autophagy through degradation of PARK7. Autophagy. 2016; 12:1215–28.
143. Wang W, Zhang F, Li L, et al. MFN2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons. J. Biol. Chem. 2015; 290:168–82.
144. Wang X, Pickrell AM, Rossi SG, et al. Transient systemic mtDNA damage leads to muscle wasting by reducing the satellite cell pool. Hum. Mol. Genet. 2013; 22:3976–86.
145. Whitman SA, Wacker MJ, Richmond SR, Godard MP. Contributions of the ubiquitin-proteasome pathway and apoptosis to human skeletal muscle wasting with age. Pflugers Arch. 2005; 450:437–46.
146. Wohlgemuth SE, Seo AY, Marzetti E, Lees HA, Leeuwenburgh C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp. Gerontol. 2010; 45:138–48.
147. Wu JJ, Quijano C, Chen E, et al. Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy. Aging (Albany NY). 2009; 1:425–37.
148. Yonashiro R, Kimijima Y, Shimura T, et al. Mitochondrial ubiquitin ligase MITOL blocks S-nitrosylated MAP1B-light chain 1-mediated mitochondrial dysfunction and neuronal cell death. Proc. Natl. Acad. Sci. U. S. A. 2012; 109:2382–7.
149. Yu H, Waddell JN, Kuang S, Bidwell CA. Park7 expression influences myotube size and myosin expression in muscle. PLoS One. 2014; 9:e92030.
150. Zhang Y, Bharathi SS, Rardin MJ, et al. SIRT3 and SIRT5 regulate the enzyme activity and cardiolipin binding of very long-chain acyl-CoA dehydrogenase. PLoS One. 2015; 10:e0122297.
Keywords:

muscle wasting; autophagy; apoptosis; aging; ubiquitin proteasome; lysosome

© 2017 American College of Sports Medicine