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Review

Autophagy in skeletal muscle

Marco Sandri *

Department of Biomedical Sciences, University of Padova, Padova, Italy Dulbecco Telethon Institute, Padova, Italy Venetian Institute of Molecular Medicine (VIMM), Padova, Italy

a r t i c l e

i n f o

a b s t r a c t

Muscle mass represents 40­50% of the human body and, in mammals, is one of the most important sites for the control of metabolism. Moreover, during catabolic conditions, muscle proteins are mobilized to sustain gluconeogenesis in the liver and to provide alternative energy substrates for organs. However, excessive protein degradation in the skeletal muscle is detrimental for the economy of the body and it can lead to death. The ubiquitin-proteasome and autophagy-lysosome systems are the major proteolytic pathways of the cell and are coordinately activated in atrophying muscles. However, the role and regulation of the autophagic pathway in skeletal muscle is still largely unknown. This review will focus on autophagy and discuss its beneficial or detrimental role for the maintenance of muscle mass. Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Article history: Received 2 January 2010 Revised 27 January 2010 Accepted 28 January 2010 Available online xxxx Edited by Noboru Mizushima Keywords: Autophagy Skeletal muscle Atrophy Protein degradation Muscle wasting Akt

1. Introduction Skeletal muscles are the body's agent of motion. In order to allow movement, the organization of muscle cells is highly structured so as to generate and sustain mechanical tension. The cytosol of myofibers is packed with contractile proteins that are assembled into repetitive structures, the basal unit of which is constituted by the sarcomere. Filaments of myosins are at the center of the sarcomere while filaments of actins are at the periphery. Several sarcomeres, arranged in register and surrounded by sarcoplasmic reticulum, form myofibrils. Various organelles such as mitochondria, for ATP generation, and sarcoplasmic reticulum, for calcium release are embedded among the myofibrils. This ordered assembly of contractile proteins and organelles differs from the cytosolic organization of the other cells of our body where mitochondria, endoplasmic reticulum and proteins move freely within the cytosol. Moreover, the myofiber is an enormous cell that can measure several centimeters in length and can contain hundreds of nuclei. It is therefore particularly difficult to visualize local as well as subtle but diffuse changes of mitochondrial and endo/sarcoplasmic reticulum networks as well as the dynamics of endocytic/exocytic

vesicles in such rigid and long structures. Several changes occur during catabolic conditions: proteins are mobilized, mitochondrial and sarcoplasmic networks are remodeled and myonuclei are lost. In addition, the daily contractions can mechanically and metabolically damage/alter muscle proteins and organelles. For example, physical exercise requires energy whose production in mitochondria can also generate reactive oxygen species (ROS) that can have deleterious effects on many cellular components. Muscle cells therefore require an efficient system for removing and eliminating unfolded and toxic proteins as well as abnormal and dysfunctional organelles. The autophagy system is responsible for this action, generating double membrane vesicles that engulf portion of cytoplasm, organelles, glycogen and protein aggregates [1,2]. Autophagosomes are then delivered to lysosomes for degradation of their contents. Despite this important function, the role of autophagy in the control of muscle mass has only recently begun to be investigated. 2. Autophagy and muscle loss Loss of muscle mass occurs in many conditions ranging from denervation, inactivity, microgravity, fasting to a multitude of systemic diseases such as cancer, sepsis, AIDS, diabetes, cardiac and renal failure [3]. In all of these catabolic conditions protein breakdown is enhanced and exceeds protein synthesis resulting in myofiber atrophy [4]. The activation of the major proteolytic

* Address: Department of Biomedical Sciences, University of Padova, Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine (VIMM), Viale Orus 2, 35129 Padova, Italy. Fax: +39 049 7923250. E-mail address: [email protected]

0014-5793/$36.00 Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2010.01.056

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systems requires a transcription-dependent program. Comparing gene expression in different models of muscle atrophy lead to the identification of a subset of genes that are commonly up- or down-regulated in atrophying muscle [5­8]. These common genes are thought to regulate the loss of muscle components and were thus designated atrophy-related genes or atrogenes [4,9]. Among these genes there are several belonging to the autophagy-lysosome system. Importantly, two autophagy genes, LC3 and Gabarap, are among the upregulated atrogenes which encode for proteins that are degraded when autophagosomes fuse with lysosomes [10­12]. Together, these data strongly suggest that autophagic flux is increased during atrophy and that this increase requires a transcriptional regulation to replenish components that are lost. Indeed, previous evidence has shown that lysosomal degradation contributes to protein breakdown in denervated muscle [13,14]. However, advances in the field were particularly slow perhaps owing to the initial difficulties of autophagosome detection within the complex structure of the myofiber. Development of biochemical and imaging tools to follow autophagosome formation greatly improved the characterisation of autophagy in atrophying muscles [15]. Mizushima et al. generated transgenic mice expressing LC3 fused with GFP [16]. LC3 is the mammalian homolog of the yeast Atg8 gene and is critical for membrane commitment and growth [17]. Activation of autophagy can be now easily visualized by the appearance of bright GFP-positive spots within myofibrils and beneath the plasma membrane of myofibers. Morphological analyses demonstrate the activation of the autophagy system during fasting in skeletal muscle. This animal model is also extremely useful for comparing the size of autophagosomes in different tissues under basal and fasted conditions. Interestingly, fasted skeletal muscle shows the smallest vesicles when compared to autophagosomes of liver, heart and pancreatic acinar cells [16]. Thus, the small size of autophagosomes could be another important aspect that, in the past, had limited the detection of autophagosomes in muscle. By using these tools we have only recently begun to unravel the contribution of autophagy to muscle loss. For example it is now known that myofiber atrophy induced in vivo by overexpression of constitutively active FoxO3 requires autophagy. Knocking down the critical gene LC3 by RNAi partially prevents FoxO3-mediated muscle loss [10]. Other genetic models have also confirmed the role of autophagy during muscle atrophy. Oxidative stress, induced by expression of mutant SOD1G93A specifically in skeletal muscle, causes muscle atrophy and weakness mainly via autophagy activation. The reduction of autophagic flux by expressing shRNAs against LC3 spares muscle mass in SOD1G93A transgenic mice [18]. However, since the preservation of muscle mass was studied by morphological observations, we do not know whether this protection is also functional and therefore, beneficial for preserving muscle force. This aspect would be important to address in the next years for the development of appropriate therapeutic approaches against weakness. Increased oxidative stress has also been reported to occur during denervation and hindlimb suspension. During these disuse conditions neuronal NOS (nNOS) moves from the sarcolemma, where it is bound to the dystrophin-glycoprotein complex, to the cytosol. Free cytosolic nNOS induces oxidative stress and enhances FoxO3-mediated transcription of the atrophy-related ubiquitin ligases, atrogin 1 and MuRF1, causing muscle loss [19]. A similar mechanism has been recently described in another model of muscle atrophy. When DHPR, a L-type Ca2+ channel, is reduced in skeletal muscles of adult animals by RNAi, it also triggers atrophy via nNOS relocalization and FoxO3 activation. However, in this genetic model of muscle atrophy, the genes that are upregulated by FoxO3 are the autophagy genes LC3, VPS34, Bnip3 and the lysosomal enzyme cathepsin L. Morphological studies of LC3 immunolocalization and ultrastructural observations by electron

microscopy confirm the induction of autophagosomes when DHPR is reduced [20]. Recent data suggest that autophagy may also contribute to sarcopenia, the excessive loss of muscle mass that occurs in the elderly [21]. During ageing there is also a progressive deterioration of mitochondrial function and activation of autophagy. Forced expression of PGC1a, the master gene of mitochondrial biogenesis, in skeletal muscles of old mice ameliorates loss of muscle mass and prevents the age-related increase of autophagy [22]. Thus, autophagy activation has been reported in acute conditions of muscle loss as well as in chronic and long-lasting situations of muscle debilitation and weakness. Interestingly, recent findings suggest that autophagy activation might be critical not only for protein breakdown and muscle atrophy but also for myofiber survival. In fact mutations that inactivate Jumpy, a phosphatase that counteracts the action of VPS34 for autophagosome formation and reduces autophagic flux, is associated with centronuclear myopathy [23]. Therefore unbalanced autophagy might be the pathogenic mechanism that causes positional alteration of myonuclei and, consequently, triggers myofiber degeneration. Together, these findings strongly suggest that excessive autophagy, similar to the ubiquitin-proteasome system, is detrimental to muscle mass.

3. Autophagy and muscle mass maintenance Autophagosomes have been found in almost every myopathy and dystrophy studied so far and are characteristic of a group of muscle disorders named Autophagic Vacuolar Myopathies (AVM) [24]. However, it is unclear whether autophagy is detrimental and part of the mechanisms that induce muscle degeneration or whether it is a compensatory mechanism for cell survival. The features of protein aggregation, abnormal mitochondria and distension of endo/sarcoplasmic reticulum that are typical of many acquired and genetic muscle diseases suggest an impairment, more than an exacerbation, of autophagic flux. For instance, protein aggregates that are positive for ubiquitin and p62/SQSTM1 proteins have been recently described in muscle of patients affected by sporadic Inclusion Body Myositis as well as in different tissuespecific autophagy knockout mice [25­27]. To clarify the role of basal autophagy we have generated two conditional knockout mice for the critical Atg7 gene to block autophagy specifically in skeletal muscle [28]. The expectation was to preserve muscle mass and eventually to gain more contractile proteins and to improve muscle strength. Surprisingly, suppression of autophagy is not beneficial and instead triggers atrophy, weakness and several features of myopathy. A similar atrophic phenotype has also been observed in muscle-specific Atg5 knockout mice, another genetic model to block autophagy [29]. Deletion of Atg7 gene causes accumulation of protein aggregates, appearance of abnormal mitochondria and of concentric membranous structures that assemble between the myofibrils or just beneath the sarcolemma, induction of oxidative stress and activation of Unfolded Protein Response. Together, these pathological conditions lead to myofiber degeneration [28] (Fig. 1). Another interesting aspect is the accumulation of polyubiquitinated proteins in detergent soluble and insoluble fractions of autophagy-null muscles. This finding has been reported in other tissuespecific autophagy knockout mice which also show an increase of polyubiquitinated proteins and accumulation of concentric membranous structures [26,27,30,31]. These observations, together with the evidence that proteasome activity is not seriously impaired in Atg7 null muscles, suggest that some ubiquitinated proteins are specifically targeted to lysosomal degradation via autophagy. We actually do not know which signals establish whether polyubiquitinated proteins are degraded via proteasome

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Fig. 1. FoxO transcription factors control the ubiquitin-proteasome and autophagy-lysosome systems. In atrophying muscles the ubiquitin-proteasome system control the half life of sarcomeric proteins. Inhibition of proteasomal-dependent degradation has been described to reduce muscle atrophy. Instead during physiological and catabolic conditions autophagosomes remove damaged mitochondria, unfolded proteins that are prone to aggregate, control the quality of the folding process in the endoplasmic reticulum (ER) and affect DNA stability. Impairing autophagy system causes accumulation of abnormal organelles and toxic proteins that leads to myofiber degeneration. The protein substrates of autophagy are poorly understood as well as the mechanisms of delivering autophagosomes to lysosomes. Inactivation of the proteins involved in the regulation of these steps causes different myopathies. In red are actions and genes whose inactivation is associated to different genetic and acquired myopathies. Dotted lines depict actions whose molecular mechanisms and role in adult skeletal muscle have yet to be completely defined.

or lysosome. A recent report has identified the enzyme sialidase Neu2 as a specific substrate of the autophagy-lysosome system in atrophying myotubes [32]. It is unclear whether decreased Neu2 protein results in non-specific engulfing of portions of the cytosol or whether specific post-translational modifications such as ubiquitination selectively brings Neu2 to autophagosomes. In fact, it is now clear that ubiquitinated proteins are delivered to autophagosomes via p62/SQSTM1 and NBR1 proteins that bind the polyubiquitin chains and LC3 [33­37]. Interestingly, the action and the ubiquitination of co-chaperones has been reported as an alternative pathway for autophagosome-dependent protein degradation in skeletal muscles. Filamin is a protein that undergoes unfolding and refolding cycles during muscle contraction and therefore is prone to irreversible damage. Alterations of filamin structure trigger the binding of the co-chaperone BAG3, which carries the complex constituted by the chaperones Hsc70, HspB8 and the ubiquitin ligase CHIP. CHIP ubiquitinates BAG3 and filamin which are recognised and delivered to the autophagy system by p62/SQSTM1 protein [38] (Fig. 1). A mutation of BAG3 that inactivates filamin removal causes a severe myopathy with Z-disk disintegration [38,39]. The process of delivering autophagosomes to lysosomes is another important step in muscle protein degradation. Recent evidence underlines an unexpected role of valosincontaining protein (VCP) in autophagosome maturation [40]. VCP/p97 is implicated in multiple processes, including cell cycle, Golgi biogenesis, nuclear envelope formation and the ubiquitinproteasome system. Mutations of VCP/p97 gene cause inclusion body myopathy (IBM), Paget disease of the bone and frontotemporal dementia (IBMPFD). Interestingly, knocking down VCP/p97 or expressing the mutant form of VCP/P97 results in accumulation of autophagosomes that fail to fuse with lysosomes [40] (Fig. 1). The accumulation of non-digested autophagosomes forms the morphological structure called rimmed vacuoles and induces the

formation of p62 positive protein aggregates. However, the mechanism by which VCP/p97 regulates autophagy is still unknown. Understanding which proteins are the substrate of autophagy and the mechanisms of their recognition and delivery to autophagosomes are intriguing questions which will hopefully gain attention in the near future. Recent findings suggest that autophagy is critical for nuclear stability (Fig. 1). Nuclear envelopathies are genetic disorders caused by mutations in the emerin and Lamin A genes that encode for structural proteins of the nucleus. These diseases are characterised by an increased nuclear fragility especially after mechanical stresses. Importantly, skeletal and cardiac muscles are the tissues that are most affected by these genetic defects. Giant autophagosomes containing nuclear components including chromatin have been found in emerin and lamin A deficient cells. Importantly, inhibition of autophagy led to accumulation of nuclear abnormalities and reduced cell viability [41]. An interest aspect that suggests a general involvement of autophagy in nuclear remodeling is the finding that similar giant autophagosomes are also present, albeit rarely, in wild type cells. Therefore, these data suggest that ``nucleophagy" may be an important mechanism for maintenance of nuclear stability in mammals. How exactly portions of nuclei are removed without affecting the number of chromosomes, genes and therefore cell viability is another crucial point that must be clarified in the near future.

4. Autophagy regulation in skeletal muscle Autophagy in skeletal muscle is peculiar when compared to other important metabolic tissues such as the liver and pancreas. During fasting most tissues show a transient activation of autophagy that only lasts a few hours. In contrast, skeletal muscle shows a

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Fig. 2. Scheme that represents positive and negative regulators of autophagy in skeletal muscle. Dotted lines depict actions whose molecular mechanisms and role in adult skeletal muscle have yet to be completely defined.

persistent generation of autophagosomes that continues for days [16]. Such prolonged autophagic induction requires transcriptional control in order to replenish LC3 and Gabarap, critical proteins that are destroyed during autophagosome fusion with lysosome. This suggests that different signaling pathways may control autophagosome formation during short (hours) or long (days) periods of induced autophagy. The balance between inhibitors and activators of autophagic machinery determines the amount of newly formed vesicles in addition to their growth, delivery and fusion with lysosomes during catabolic conditions. In skeletal muscles, few autophagy suppressors have been reported, the first of which was Runx1. In fact, denervation is able to induce autophagy in skeletal muscles, although at a slower rate than fasting [42,43]. This effect is mediated by Runx1, which is upregulated in denervated muscles and is required to preserve muscle mass [44]. In fact, Runx1 ablation results in excessive autophagy during denervation which leads to severe atrophy [44]. The mechanisms of Runx1mediated autophagy suppression is unclear but recent evidence shows that Runx1 can modulate FoxO3 action [45]. In hepatic cell lines Runx1 interacts with FoxO3 promoting FoxO3 recruitment to the Bim promoter [45]. It is of interest understanding whether upregulation of Runx1 in denervated muscles negatively affects FoxO3 recruitment to the promoters of autophagy genes and in doing so reduces autophagy flux. Another negative regulator of autophagy in muscle cells is the phosphatase Jumpy. Reduction of Jumpy protein by RNAi results in the formation of autophagosomes in C2C12 myoblasts and an increased rate of proteolysis observed both in normal and starvation media [23]. Jumpy blocks autophagosome formation by reducing the levels of PI3P and therefore counteracting the action of the class III PI3 kinase, VPS34. However, the regulation of Jumpy in normal and atrophic muscles is still unknown. The most potent autophagy inhibitor in skeletal muscles is the kinase Akt. Acute activation of Akt in adult mice or in muscle cell cultures completely inhibits autophagosome formation and lysosomal-dependent protein degradation during fasting [10­12,46]. Mammalian TOR (mTOR) is a nutrient-sensitive kinase downstream of Akt that is important for cell growth. In fact muscle hypertrophy requires mTOR since treatment with rapamyicin, an

mTOR inhibitor, completely blocks muscle growth of adult or regenerating myofibers [47,48]. However, the role of mTOR in autophagy regulation is much less important and therefore, mTOR, at least in skeletal muscles, does not mediate the negative effect of Akt on the autophagy pathway. Accurate biochemical studies have determined that rapamycin-mediated mTOR inhibition only barely (10%) increases protein breakdown in differentiated myotubes. This response is much smaller than the 50% increase of protein breakdown induced by Akt inhibition [12]. Importantly, in vivo inhibition of mTOR by rapamycin and by RNAi is not sufficient to induce atrophy and autophagosome formation [10,12,49]. Furthermore, the deletion of mTOR gene specifically in skeletal muscles leads to muscular dystrophy rather than atrophy [50]. However, it is important to underline that mTOR deletion, similar to RAPTOR and RICTOR deficient muscles [51], causes a hyperactivation of Akt. The hyperphosphorylation of Akt can blunt or mitigate the effects of mTOR ablation on the autophagy system. However, previous studies have confirmed an mTOR-independent but VPS34-beclin1-dependent control of the autophagic system in myotubes [52,53]. Moreover, deletion of S6K1, a downstream target of mTOR, and of S6K2 does not affect the autophagic flux in cultured myotubes [54]. Therefore, the inhibition of the IGF1-Akt pathway during fasting must stimulate autophagy mainly via mTOR-independent mechanisms. The upregulation of several autophagy-related genes in atrophying muscles [7,10,12,42,43] suggests the contribution of one or more transcription factors to autophagy regulation. We recently identified FoxO3 as the critical factor for autophagy control in adult muscles. Expression of FoxO3 is sufficient and required to activate lysosomal-dependent protein breakdown in cell culture and in vivo. Moreover several autophagy genes including LC3, Gabarap, Bnip3, VPS34, Atg12 are under FoxO3 regulation. Gain and loss of function experiments identified Bnip3, a BH3-only protein, as a central player downstream of FoxO [10,55]. Indeed, Bnip3 is regulated by DAF-16, the homolog of FoxO, in Caenorhabditis elegans [56] and overexpression of Bnip3 induces mitochondrial fragmentation and autophagy in cardiomyocytes exposed to ischemia/ reperfusion conditions [57]. Overexpression of Bnip3 per se is able to induce autophagy in skeletal muscle in vivo whereas Bnip3

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knockdown reduces FoxO3-induced autophagy [10]. The FoxOdependent regulation of autophagy seems to be a general mechanism to sustain autophagy for long periods. In fact FoxO-dependent transcriptional upregulation of several autophagy-related genes have been described in Drosophila larval fat body [58], mammalian cardiomyocytes [59,60], hepatocytes [61], colorectal cancer cells [62] and during cellular senescence [63]. The contribution of each FoxO member to autophagy regulation must be better analyzed by loss of function approaches. Recently, the p38 ab MAPK pathway was also described to regulate expression of autophagy-related genes independently of FoxO3 during oxidative stress [64]. However, the specific transcription factors downstream of p38MAPK that induce autophagy in atrophying myotubes remains unclear. The interplay between FoxO transcription factors and p38MAPK must be better clarified in the future since an opposing conclusion was reached in a recent paper. In this case, p38 MAPK inhibition triggered autophagy-related gene expression via AMPK-FoxO3 axis in colorectal cancer cells [62]. The picture of both positive and negative modulators of the autophagy system in skeletal muscle is just at the beginning (Fig. 2) and will need to be better defined and completed in the coming years. 5. Conclusions The autophagy-lysosome system is emerging as a crucial system that controls muscle mass during catabolic conditions. However, the autophagy system is also required for basal myofiber homeostasis and its inhibition can lead to myofiber degeneration. We therefore need a more precise understanding of the signaling pathways that control the autophagy system and its interrelation with the ubiquitin-proteasome pathway. Indentifying the muscle proteins that are targeted to autophagy and uncovering the molecular mechanisms that deliver them for lysosomal degradation are additional important issues that need to be addressed in the coming years. Acknowledgments I apologize to colleagues whose studies were not cited owing to space limitations. Our work is supported by grants from ASI (OSMA project), Telethon-Italy (TCP04009), from the European Union (MYOAGE, contract: 223576 of FP7), AFM (14135), the Italian Ministry of Education, University and Research (PRIN 2007). The critical reading of Kenneth Dyar is gratefully acknowledged. References

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