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Mitophagy Regulation in Skeletal Muscle: Effect of Endurance Exercise and Age

  • Avigail T. Erlich
  • David A. HoodEmail author
Review Article
  • 50 Downloads

Abstract

Mitochondria are essential energy-providing organelles that are required in the maintenance of healthy skeletal muscle. As such, the removal of damaged mitochondria, through mitophagy, is necessary to maintain mitochondrial quality. In aging muscle, mitochondrial content and function are often found to be reduced compared to young individuals. This occurs despite the fact that measures of mitophagy are elevated, suggesting that mitophagy is insufficiently high to remove all of the dysfunctional organelles in aging muscle. Recent evidence has shown that acute exercise promotes mitophagic signaling, leading to organelle degradation. This exercise-induced signaling is attenuated in aging muscle, suggesting that aging muscle loses its capacity for mitochondrial turnover in response to exercise. This contributes to the reduction in muscle health in elderly individuals. Chronic exercise training improves mitochondrial content and function, even in aging muscle, leading to reduced mitophagy signaling. Thus, exercise training should be prescribed for both young and elderly populations to promote the maintenance of a healthy mitochondrial pool, through the stimulation of both organelle biogenesis and mitophagy.

Keywords

Mitochondria Mitophagy Exercise Aging Lysosomes 

Abbreviations

AMP

Adenosine monophosphate

AMPK

AMP-activated protein kinase

LC3

Microtubule-associated proteins 1A/1B light chain 3A

LAMP 1/2

Lysosomal-associated membrane proteins 1 and 2

MIT/TFE

Microthalmia-transcription factor E

mTORC1

Mammalian/mechanistic target of rapamycin complex 1

NUGEMP

Nuclear gene-encoded mitochondrial protein

PGC-1α

Peroxisome proliferator activator receptor (PPAR) coactivator 1 alpha

PINK1

PTEN-induced putative kinase 1

p38MAPK

p38 mitogen-activated protein kinase

TFEB

Transcription factor EB

ULK1

Serine/threonine protein kinase

Regulation of mitochondrial content in muscle

Skeletal muscle comprises approximately 40% of the adult human body mass in non-overweight individuals. The primary function of skeletal muscle is to convert chemical energy, in the form of ATP, into mechanical energy to generate force, maintain posture, and produce movement [16, 47]. Muscle is a highly malleable tissue, and it exhibits remarkable capabilities to adapt to a number of physiological and pathological conditions. ATP supply under steady-state and aerobic conditions is provided by mitochondrial oxidative phosphorylation. This process within mitochondria is tightly regulated and responds quickly to muscle demands for more ATP. Thus, the maintenance of a healthy pool of mitochondria is vital for muscle health. The morphology of mitochondria is largely that of a reticulum, or network, which extends beneath the sarcolemma and between the myofibrils. This morphology relies on the dynamic interplay between fission and fusion processes. The fusion of smaller mitochondria to the larger reticular network occurs with the aid of mitofusion 1/2 (Mfn1 and Mfn2) as well as optical atrophy 1/2 (Opa1 and Opa2). This fusion allows for the organelles to share mitochondrial material and expand the mitochondrial network. Alternatively, fission works to break down the reticulum into smaller fragmented organelles to remove dysfunctional mitochondria for degradation [21, 22, 33] The main proteins involved in fission are dynamin-related protein 1 (Drp1), which resides on the mitochondrial outer membrane, and fission protein 1 (Fis1), which ultimately serves to constrict the mitochondria to promote the separation of dysfunctional portions of the organelle [11, 19, 33, 41, 46]. The expansion of the reticulum and removal of dysfunctional organelles are governed by two opposing processes [33]. The first of these is termed mitochondrial biogenesis, referring to an expanded mitochondrial network [17]. This process is controlled by the coordinated expression of nuclear and mitochondrial genes, and regulated in part by the coactivator PGC-1α [18, 27, 48, 59], along with other transcription factors. The opposing process mediating mitochondrial content is organelle-specific autophagy, termed mitophagy. The removal of dysfunctional mitochondria is as important as biogenesis, ensuring organelle quality control. Impairments in this process are characterized by the presence of abnormal mitochondria, accumulation of polyubiquitinated proteins, and structural defects [47]. This is especially evident with aging, where age-induced mitochondrial ROS production, increased mtDNA mutation rate, and mitochondrial dysfunction are considered potential causes of sarcopenia [16, 46, 63].

General Autophagy Pathway

Organelle degradation is mediated by autophagy, where double membrane vesicles known as autophagosomes engulf damaged organelles and fuse with a lysosomal membrane where these organelles are digested [28, 49, 57]. This process involves distinct steps, including induction, cargo recognition and selection, vesicle formation, autophagosome–vacuole fusion resulting in breakdown of the cargo, and the release of the degradation products back into the cytosol (Fig. 1). Autophagy begins with an isolation membrane, known as a phagophore expanding to engulf the intracellular cargo (such as mitochondria) and form a double-membraned autophagosome. This cargo-containing autophagosome then travels on microtubule tracks to fuse with lysosomes. Lysosomes degrade cellular cargos when they become defective. They contain pH-dependent enzymes for the breakdown of macromolecules and organelles. They also possess a number of lysosome-associated membrane proteins (LAMPs) that are involved in autophagosome–lysosome fusion [14, 26, 28, 49, 56]. Lysosomal permeases and transporters then export amino acids and other by-products of degradation back out to the cytoplasm, where they can be re-used for building macromolecules or for metabolism (Fig. 1) [7, 12]. Thus, autophagy may be thought of as a cellular “recycling process” that also promotes energy efficiency through ATP generation, and mediates damage control by removing non-functional proteins and organelles.
Fig. 1

Degradation of dysfunctional mitochondria through mitophagy in young and aged muscle with acute exercise or endurance training. a Under basal conditions in young muscle, dysfunctional mitochondria produce higher amounts of ROS and exhibit a lower membrane potential, causing an accumulation of Pink1 on the outer mitochondrial membrane. Pink1 recruits the E3 ubiquitin ligase Parkin which ubiquitinates outer mitochondrial proteins such as Mfn2 and VDAC. Ubiquitination of these proteins recruits the adaptor protein p62. LC3I lipidation to LC3II allows for the initial formation of the autophagosome, which is recruited to mitochondria through an interaction of LC3II with p62. The autophagosome then engulfs the mitochondria. Under the same conditions, TFEB translocates to the nucleus and binds to the CLEAR network upstream region. This promotes the transcription of lysosomal and autophagy-related genes, and the formation of more lysosomes. The autophagosome then fuses with the lysosome with the aid of LAMP1. Protease activity within the lysosome subsequently degrades mitochondria. b Acute exercise in young muscle increases signaling for mitophagy by targeting the mitochondria for degradation (arrow left), augmenting mitochondrial engulfment within autophagosomes. Concurrently, there is an increase in signaling promoting the transcription of lysosomal genes and subsequently the formation of new lysosomes (arrow right). This ultimately leads to amplified mitochondrial degradation by lysosomes. Future work investigating lysosomal biogenesis signaling with acute exercise is warranted (indicated by “?”). c Endurance training in young muscle also increases signaling to mitophagy and lysosomal genes. While there is an increase in lysosomes with endurance training, the need for mitophagy is reduced due to a healthier pool of mitochondria. Therefore, there is a reduction in mitochondrial degradation, despite a greater capacity for degradation in the presence of more lysosomes. d Aged skeletal muscle exhibits an increase in mitophagy signaling under basal conditions compared to young muscle (thicker arrows) due to higher amounts of dysfunctional mitochondria. Despite an increase in lysosomal proteins, some lysosomes appear to be defective (gray lysosomes), ultimately leading to impaired mitochondrial degradation. e Acute exercise appears to have an attenuated effect on mitophagy in aged muscle. f With endurance training, aging muscle still exhibits high signaling for mitochondrial targeting for mitophagy. However, this does not lead to an increase in mitochondrial flux, exhibited by lower amounts of mitochondria within autophagosomes, possibly due to healthier mitochondria after training. Despite lower levels of TFEB protein, levels of lysosomal markers remain high with training, potentially leading to healthier lysosomal machinery

Mitophagy Pathways

Several mitophagy pathways are involved in the clearance of dysfunctional mitochondria. The canonical, and most well-established pathway involves PTEN-induced putative kinase protein 1 (PINK1) and Parkin. Under stable conditions when mitochondria are functioning properly, PINK1 is imported into mitochondria and is degraded by proteases [14, 60]. However, when there is a reduction in the mitochondrial membrane potential, the import machinery loses its functionality, and PINK1 accumulates and stabilizes on the outer mitochondrial membrane [37]. This PINK1 accumulation facilitates the recruitment of the E3-ubiquitin ligase Parkin to mitochondria. Parkin then mediates the ubiquitination of various outer membrane proteins, targeting them for degradation. Among these proteins are those involved in mitochondrial fusion, such as mitofusin1 (MFN1) and mitofusin 2 (MFN2) [55], as well as other outer mitochondrial membrane proteins such as the voltage-dependent anion channels (VDAC), translocase of the outer membrane proteins (TOMs), and many others. Ubiquitination of these proteins recruits the adapter protein p62/SQSTM1. p62 contains both ubiquitin and microtubule-associated protein 1 light chain 3 (LC3) interacting domains [14], serving as an anchor and allowing the formation of an autophagic double membrane around the dysfunctional mitochondrion [56]. The autophagic vesicle begins once LC3I is lipidated into LC3II with the aid of other autophagy-related genes such as ATG 7 [56]. Once lipidated, LC3II is able to interact with p62 and an autophagosome fully engulfs the organelle. The autophagosome travels on microtubule tracks and with the help of lysosomal-associated membrane proteins 1 and 2 (LAMP1 and LAMP2), it fuses with the lysosome (Fig. 1) [13].

Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and BNIP3-like protein X (NIX) were originally recognized for their role in mitochondrially induced apoptosis, however, recent evidence has demonstrated their involvement in the process of mitophagy, and these proteins constitute an alternative pathway [15, 61]. BNIP3 and NIX localize to the outer membrane of dysfunctional mitochondrion and flag it for degradation. Both proteins possess an LC3 interacting region, and are able to act as receptors for LC3 family members to allow for the formation of the autophagosome. Furthermore, BNIP3 has the ability to recruit dynamin-related protein 1 (Drp1) to the mitochondria, thus activating fission and stimulating parkin-mediated autophagy [33]. The cellular events that trigger this alternative pathway are not fully resolved in skeletal muscle.

TFEB/TFE3

The autophagy process is able to target damaged organelles with the aid of receptors and signaling components. The autophagosome and lysosome comprise the two main organelles that ensure this process is completed adequately. Recent work has identified a regulatory set of genes known as the coordinated lysosomal enhancement and regulation (CLEAR) network, which controls the transcription of lysosomal genes. The master proteins regulating this network are the four members of the basic helix loop helix (bHLH)-leucine zipper transcription factors MiT and TFE. These include TFEB, TFE3, MITF and TFEC [51, 53], and all share a basic motif, required for DNA binding, and a similar HLH–LZ region that is important for their dimerization. Recent evidence has identified TFEB and TFE3 as the main regulators of lysosomal homeostasis and autophagy induction within this transcriptional family [53, 62].

TFEB and TFE3 directly bind to CLEAR elements, thus activating the expression of the entire network of genes that contains the CLEAR regulatory motif in their promoters [53, 62]. Therefore, it is not surprising that TFEB and TFE3 overexpression results in an increased number of lysosomes and lysosomal enzymes which serve to enhance catabolic activity [53, 62]. In contrast, the depletion of these transcription factors abolishes the enhanced expression of lysosomal genes. In addition to regulating lysosomal biogenesis, TFEB has also been shown to coordinate the expression of genes involved in autophagosome biogenesis and lysosome fusion, indicated by an increased clearance of lipid droplets and mitochondria with TFEB overexpression [35, 38, 42].

TFEB Activation

Nutritional stressors such as fasting and caloric restriction regulate the quality control of organelles such as mitochondria via autophagy, and TFEB is regulated by such conditions of nutrient deprivation [38, 39]. TFEB activity is mainly controlled via its phosphorylation status. Under basal conditions, phosphorylated TFEB is sequestered in the cytosol where it remains inactive. However, dephosphorylation causes its activation and subsequent translocation into the nucleus [35, 42, 62]. The phosphorylation of TFEB is mediated by mTORC1, a growth regulator and which responds to amino acids arising from within the lysosomal lumen. When amino acids are released from the lysosome under high nutrient conditions, they activate Rag GTPases [40, 52]. These Rag proteins interact with a complex known as Regulator. This complex binds to raptor on mTORC1 and promotes its translocation from the cytosol to the lysosomal membrane where it interacts with Rheb, an activator of mTORC1 [31, 35, 40, 53, 66]. TFEB is then recruited to the lysosome through an interaction with mTORC1, which phosphorylates TFEB on ser211. Once phosphorylated, TFEB is detained in the cytosol by the chaperone 14-3-3 [31, 38, 40]. During starvation conditions, TFEB is liberated from this chaperone and can translocate to the nucleus to stimulate the expression of autophagy–lysosomal genes [38, 40, 51].

An additional pathway was found originating from the lysosome which controls TFEB sublocalization through its dephosphorylation via calcium signaling. Calcineurin is a calcium-activated phosphatase able to dephosphorylate TFEB on ser211and ser142 [12, 45, 65]. Inhibition of calcineurin by cyclosporine A or FK506 reduces TFEB translocation to the nucleus. Furthermore, in vivo studies have revealed that transfection of mice with activated calcineurin promoted TFEB translocation, and exercise, a known activator of calcineurin, had the same effect [12, 38, 39]. During starvation and exercise, calcineurin activity is locally induced near the lysosome by lysosomal calcium release through the lysosomal MCOLN1/mucolipin Ca2+channel. Experiments conducted both in vitro and in vivo demonstrated that shRNA-mediated inhibition of MCOLN1 significantly reduced TFEB translocation to the nucleus. In contrast, overexpression of MCOLN1 in HeLa cells increased the shuttling of TFEB from the cytosol to the nucleus [38, 39]. Overall, it seems that two independent pathways mediated by lysosomal signaling mediate the regulation of TFEB. Conditions of energy deficits, such as starvation, or energy utilization, such as exercise cause a decreased rate of TFEB phosphorylation, through mTORC1 inhibition, and an induction of TFEB dephosphorylation by calcineurin [12, 38, 39, 45, 65].

TFEB and Exercise

During an acute bout of exercise, the release of calcium from the sarcoplasmic reticulum increases levels of cytosolic calcium, promoting a signaling pathway involved in mitochondrial biogenesis [4, 20, 23, 36]. Calcium also acts as an activator of calcineurin, which subsequently dephosphorylates TFEB and allows its translocation to the nucleus. Recent studies have investigated this pathway in mice subjected to a bout of exercise. TFEB translocation occurred during exercise, however, this effect was blunted when the calcineurin inhibitor CAIN was electroporated into the muscle. This suggests that exercise acts as a stimulus for the induction of TFEB activity via Ca2+-induced calcineurin activity [39, 59]. This may contribute to the increase in the expression of autophagy genes, a result that was demonstrated after an acute bout of exercise in heart and skeletal muscle [23, 39]. This likely drives the increase in autophagy flux that occurs to mediate the turnover of damaged organelles.

Effect of Acute Endurance Exercise on Mitophagy

It is well known that exercise has multiple beneficial health effects. Engaging in regular exercise facilitates an improvement in glucose homeostasis, cardiovascular health, the maintenance of muscle mass, and can help reduce complications that occur with aging [2, 6, 19, 26, 28, 43, 57]. On a molecular level, regular exercise exerts favorable effects on bioenergetics and nutrient delivery and uptake, which largely occur due to the accumulated adaptation of muscle in response to individual acute exercise bouts [18, 19, 48]. Regularly performed exercise results in a large increase in mitochondrial content via an induction of organelle biogenesis [18, 47]. While it is important to ensure there is a sufficient increase in mitochondrial synthesis, it is also vital to remove any dysfunctional mitochondria that are no longer functional to satisfy the elevated energy demands of exercise [11, 58].

Mitophagy has received considerable attention recently as a cellular homeostasis response, since protein and organelle recycling are important for cellular health. This process is ongoing at a basal level, but it is upregulated as a result of increased oxidative stress, energetic imbalance, or protein misfolding, in an attempt to improve and maintain mitochondrial quality [11]. In keeping with this, it has been documented that both acute exercise, and exercise training, are able to activate the mitophagy pathway [34, 58]. During exercise, the increased energy demand results in accelerated ATP turnover, causing the ATP/AMP ratio to decrease thereby activating AMPK, an established activator of mitophagy. At the same time, exercise may reduce the activity mTORC1, a known inhibitor of the process. In addition, ROS production increases with exercise, further activating AMPK and p38 MAPK, as well as sirtuin-1 (SIRT1) activity [1, 5, 44]. These metabolic alterations occurring with exercise and the function of these proteins has been extensively studied with respect to mitochondrial biogenesis [19, 27, 59], however, their role in mitophagy is also vital for mitochondrial health. The role of AMPK and its downstream target ULK1 in this process of mitophagy has been investigated using the pMitoTimer reporter gene in vivo [30]. These researchers found that both AMPK and ULK1 were phosphorylated following acute treadmill exercise, which led to an increase in mitophagy during the post-exercise recovery period. Others have shown that acute exercise produces an immediate increase in Parkin localization to mitochondria, as well as an increase in mitophagy flux, measured via LC3-II, p62, and ubiquitin [7, 9, 10].

Recent work by Vainshtein et al. [59] has also demonstrated that PGC-1α, the master regulator of mitochondrial biogenesis, has also been implicated in mediating exercise-induced mitophagy [9, 10, 59], suggesting that it is a novel player in mediating mitochondrial turnover. This study established that mitophagy signaling and flux are induced with an acute bout of exercise, however, this effect was not apparent during exercise in PGC-1α KO animals. Acute exercise is also capable of enhancing the activation and localization of TFEB to the nucleus. Erlich et al. [12] found an increase in TFEB nuclear translocation and TFEB transcription following acute treadmill exercise, as well as after contractile activity in cultured myotubes. These increases were likely due to transient Ca2+ fluxes and subsequent calcineurin activation, since inhibition of calcineurin prevented TFEB translocation to the nucleus. Another mechanism that may be involved in the contractile activity induced increase in AMPK phosphorylation, which can negatively regulate mTORC1 function [3, 23]. This inactivation of mTORC1 may reduce TFEB phosphorylation, thereby promoting its nuclear localization, an effect that was not apparent in PGC-1α KO mice, suggesting an additional role for PGC-1α as an enhancer of TFEB-mediated autophagic induction [12].

The role and importance of Parkin in acute exercise-induced mitophagy have been studied utilizing Parkin KO mice. Parkin activation during exercise is thought to be the result of an increase in oxidative stress and a loss of membrane potential, which results in the stabilization of PINK1 on the mitochondrial outer membrane [27, 60]. Parkin is then recruited by PINK1 to ubiquitinate outer mitochondrial membrane proteins, ultimately leading to autophagosome formation around the organelle [58]. Although Parkin KO mice showed no difference in mitophagic LC3II, p62 and ubiquitin flux under basal conditions, Parkin was required for the increase in mitophagy observed with exercise [9, 10]. In addition, Parkin may also function independently of PINK1, since it has been reported that PINK1 is not localized to the mitochondria during exercise [37].

Effect of Chronic Exercise on Mitophagy

Chronic exercise training is known to induce long-term biochemical and morphological adaptations. These alterations include enhanced mitochondrial content brought upon by changes in both mitochondrial biogenesis and mitophagy [3, 43]. Ju et al. [24] and Lira et al. [34] have found an increase in autophagy and mitophagy markers with exercise training. However, as noted above, these are indirect measures of mitophagy [7, 9, 10, 28]. Chen et al. [9, 10] provided a direct measurement of mitophagy flux utilizing colchicine treatment with 6 weeks of voluntary wheel training. They found enhanced localization of Parkin to the mitochondria, as well as an increase in Parkin expression in muscle of trained mice. This was accompanied by an attenuation of exercise-induced mitophagy flux in trained muscle. Other experiments have used chronic contractile activity (CCA) as an alternate model of endurance training, wherein the muscle is electrically stimulated for 7–10 days to produce a training effect. Studies using CCA have found that basal mitophagy flux was reduced after training. The authors concluded that exercise training led to an improvement in mitochondrial function, thereby reducing the signaling pathway that induces mitophagy, as a result of better organelle quality [7, 28].

As previously mentioned, lysosomes play an important role in the process of mitophagy, as does their transcriptional regulator TFEB. Chronic contractile activity in vivo has been shown to result in significant elevations in TFEB protein and nuclear TFEB accumulation [26, 35]. Furthermore, the protein contents of the lysosomal markers Cathepsin D, MCOLN1, LAMP1 and LAMP2 were elevated by this treatment. These results support the idea that chronic exercise induces the expression of lysosomes and autophagy-related genes, which increase the capacity of the trained muscle to clear dysfunctional organelles and other cargo, including mitochondria.

Mitophagy and Aging

Advancing age is associated with a reduction in muscle performance and mass known as sarcopenia. Mitochondria have been implicated in the process of aging-led sarcopenia, as they exhibit dysfunctional properties and increased ROS emission. The accumulation of ROS in aging muscle causes the activation of FOXO pathways [7, 25, 50], leading to apoptosis, protein degradation, skeletal muscle atrophy and ultimately muscle dysfunction. This ROS production is also associated with mutations in mitochondrial DNA, which results in mutated electron transport chain (ETC) proteins [16, 63]. With a defective ETC, there is a disruption in oxidative phosphorylation, reduction in ATP synthesis, and an even further increase in ROS [19, 46]. An increase in ROS emission from mitochondria will also disrupt the protein import process and trigger Pink1-Parkin-mediated mitophagy.

Current research provides contrasting theories between the relationship of aging and autophagy in muscle. Some literature states that autophagy in muscle is attenuated with age, leading to an accumulation of dysfunctional mitochondria [27, 54]. This appears to be based on the measurement of increased levels of p62 and LC3-II proteins with age, which are normally degraded by autophagy. However, it is now recognized that the measurement of upstream autophagy protein levels does not provide a complete picture of the process. Autophagy is highly dynamic, and static measurements of these proteins can be interpreted in several ways [29, 64]. Therefore, the quantification of autophagy using autophagosome flux is now regarded as the standard technique. Drugs which inhibit autophagosome transport on microtubule tracks, such as colchicine, or those impair lysosome acidification, such as chloroquine, have been used as standard practice to estimate flux in experimental conditions, when compared with vehicle controls [8, 9, 10].

Following the treatment of animals or cells, with agents such as those described above, mitochondria are isolated, and the extracts are used to assess the organelle-specific localization of mitophagy markers. Using these techniques, it was revealed that aged muscle actually exhibited greater LC3-II mitophagy flux than young muscle. This was supported by enhanced p62 mitophagy flux and localization on mitochondria, as well as the elevated expression of mitophagy receptors in mitochondria of aged muscle. Researchers have also found an increase in total Parkin [6, 9, 10, 32] with aging, as well as increased Parkin ubiquitination on mitochondria [9, 10], suggestive of greater mitophagy. The higher mitophagy in aged muscle is consistent with evidence of reduced mitochondrial content in this tissue. However, mitochondrial dysfunction remains increased with age, which could indicate that, despite the elevations in mitophagy in an attempt to maintain a high-quality mitochondrial pool, this increase remains insufficient. Therefore, as the increase in mitochondrial dysfunction cannot be entirely eliminated by mitophagy, skeletal muscle mitochondria still exhibit an increase in ROS, ultimately leading to the sarcopenia evident in old age.

Another identifiable characteristic of aging muscle is the attenuation of exercise-induced mitophagy flux. Chen et al. found that the induction of LC3II and p62 mitophagic signaling was reduced after an acute bout of exercise in aged muscle compared to young mice, indicative of a lower rate of mitophagy [9, 10]. This fortifies the idea that exercise-induced signaling to mitophagy or other cellular processes, such as transcription, is not as prominent in aged muscle [19]. Carter et al. [7] also found that CCA was able to decrease mitophagy flux in both young and aging muscle, indicating that endurance exercise is able to reduce the mitophagy signaling in the presence of improved mitochondrial quality, even in aged muscle. Thus, repeated bouts of acute exercise exert a beneficial effect in initiating signaling leading to the degradation of dysfunctional segments of the mitochondrial reticulum in muscle, ultimately leading to a healthier mitochondrial pool in both young and aging muscle.

Conclusion

The regulation of mitochondrial quality control in muscle is maintained by a balance of mitochondrial biogenesis and degradation via mitophagy. While the synthesis of new mitochondria is extremely important, impairments in mitophagy lead to dysfunction and defective mitochondria. While organelle degradation is ongoing at a basal level, the process is augmented with an increase in oxidative stress or energy imbalance to try to maintain mitochondrial quality. An acute exercise bout is known to cause elevated energy demands and activate the mitophagy pathways to remove dysfunctional mitochondrial segments [9, 10, 59]. Similarly, exercise training is also able to enhance the expression of lysosomes and autophagy-related genes. This allows for an improved capacity of the trained muscle to clear dysfunctional organelles and other cargo, including mitochondria. Paradoxically, higher mitophagy is also seen in aging muscle, consistent with reduced mitochondrial content. Despite this, defective mitochondria persist in aging muscle, suggesting that this increase is insufficient to maintain a healthy organelle pool. Repeated bouts of acute exercise activate both mitochondrial biogenesis and mitophagy pathways and lead to an adaptive improvement in mitochondrial quality, even in aged muscle. Figure 1 is a visual representation summarizing the points discussed in this review. Future work should be devoted to examining the effect of exercise and training on lysosomal function and degradation capacity to provide a more complete assessment of mitophagy flux in young and aged skeletal muscle.

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Copyright information

© Beijing Sport University 2019

Authors and Affiliations

  1. 1.Muscle Health Research Centre, School of Kinesiology and Health ScienceYork UniversityTorontoCanada

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