**Autophagy, a Highly Regulated Intracellular System Essential to Skeletal Muscle Homeostasis — Role in Disease, Exercise and Altitude Exposure**

Anthony M.J. Sanchez, Robin Candau, Audrey Raibon and Henri Bernardi

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60698

#### **Abstract**

nated proteins and their potential role in muscle damage in Pompe disease. Hum.

[124] Vainshtein A, Grumati P, Sandri M, Bonaldo P (2014) Sakeletal muscle, autophagy, and physical activity: the ménage á trois of metabolic regulation in health and dis‐

[125] Irwin WA, Bergamin N, Sabatelli P, Reggiani C, Megighian A, Merlini L, Braghetta P, Columbaro M, Volpin D, Bressan GM, Bernardi P, Bonaldo P (2003). Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency. Nat. Gen‐

[126] Vergne I, Roberts E, Elmaoued RA, Tosch V, Delgado MA, Proikas-Cezanne T, La‐ porte J, Deretic V (2009) Control of autophagy initiation by phosphoinositide 3-phos‐

[127] De Palma C, Morisi F, Cheli S, Pambianco S, Cappello V, Vezzoli M, Rovere-Querini P, Moggio M, Ripolone M, Francolini M, Sandri M, Clementi E (2012) Autophagy as a new therapeutic target in Duchenne muscular dystrophy. Cell Death Dis. 3: e418.

[128] Ramos FJ, Chen SC, Garelick MG, Dai DF, Liao CY, Schreiber KH, MacKay VL, An EH, Strong R, Ladiges WC, Rabinovitch PS, Kaeberlein M, Kennedy BK (2012) Rapa‐ mycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues car‐ diac and skeletal muscle function, and extends survival. Sci. Transl. Med. 4: 144ra103.

[129] Carmignac V, Svensson M, Körner Z, Elowsson L, Matsumura C, Gawlick KI, Alla‐ mand V, Durbeej M (2011) Autophagy is increased in laminin α2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of

[130] Sakuma K, Yamaguchi A (2012) Cellular and molecular mechanism regulating hy‐ pertrophy and atrophy of skeletal muscle. Skeletal Muscle: Physiology, Classification

and Disease, 141-193, ed: Willems M. Nova Science Publisher, NY.

Mol. Genet. 17: 3897-3908.

ease. J. Mol. Med. 92: 127-137.

phatase Jumpy. EMBO J. 28: 2244-2258.

MDC1A. Hum. Mol. Genet. 20: 4891-4902.

et. 35: 361-371.

170 Muscle Cell and Tissue

Autophagy is an evolutionarily conserved intracellular system that selectively eliminates protein aggregates, damaged organelles, and other cellular debris. It is a self-cleaning process critical for cell homeostasis in conditions of energy stress. Autophagy has been until now relatively overlooked in skeletal muscle, but recent data highlight its vital role in this tissue in response to several stress conditions. The most recognized sensors for autophagy modulation are the adenosine monophos‐ phate (AMP)-activated protein kinase (AMPK) and the mechanistic target of rapamycin (MTOR). AMPK acts as a sensor of cellular energy status by regulating several intracellular systems including glucose and lipid metabolisms and mitochon‐ drial biogenesis. Recently, AMPK has been involved in the control of protein synthesis by decreasing MTOR activity and in the control of protein breakdown programs. Concerning proteolysis, AMPK notably regulates autophagy through FoxO transcrip‐ tion factors and Ulk1 complex. In this chapter, we describe the functioning of the different autophagy pathways (macroautophagy, microautophagy, and chaperonemediated autophagy) in skeletal muscle and define the role of macroautophagy in response to physical exercise, a stress that is well assumed to be a key strategy to counteract metabolic and muscle diseases. The effects of dietary factors and altitude exposure are also discussed in the context of exercise.

**Keywords:** Cachexia, Endurance exercise, Hypoxia, Proteolysis, Sarcopenia

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **1. Introduction**

Skeletal muscle exhibits remarkable adaptive capabilities in response to various stimuli such as loading conditions (resistance training, microgravity), contractile activity (electrical stimulations, endurance exercise), environmental factors (altitude exposure), or nutritional interventions. To access this great capacity, a plethora of quantitative and functional adaptations are involved. Changes in the size of adult muscle, in response to these external stimuli, are mainly due to the growth of individual muscle fibers rather than an increase in fiber number [1].

The control of muscle mass is dependent upon a balance between anabolic and catabolic processes. Hypertrophy is associated with increased protein synthesis, while atrophy is characterized by increased degradation of muscle proteins and/or a decrease in protein translation. The initiation of protein synthesis is mainly mediated by a signaling pathway in which the mammalian/mechanistic target of rapamycin complex 1 (MTORC1), a multiprotein complex composed of MTOR (mammalian/mechanistic target of rapamycin), RPTOR (regu‐ latory-associated protein of MTOR), mLST8/GβL (MTOR-associated protein LST8 homolog), DEPTOR (DEP domain containing MTOR-interacting protein), and PRAS40 (proline-rich Akt substrate of 40 kDa) [2,3]. MTORC1 by phosphorylating its substrates S6K1 (ribosomal protein p70S6 kinase 1) and 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1) controls skeletal muscle protein translation and hypertrophy [4-7]. The Insulin signaling pathway leads to the activation of MTORC1 through the activation of the kinases PI3K (phosphatidylinositol 3-kinase), PDK1 (phosphoinositide-dependent kinase-1), and Akt. Akt, also known as protein kinase B (PKB), inactivates tuberous sclerosis complex 1/2 (TSC1/2), promoting MTOR activation by Rheb-GTP [8-10]. Akt also phosphorylates and inactivates the glycogen synthase kinase 3β (GSK3β), resulting in the activation of the eukaryotic translation initiation factor 2B (eIF2B) and increased protein synthesis [5,11].

Muscle atrophy leads to a state of weakness and emaciation of the body, which is encountered, for example, in the terminal phase of certain diseases or chronic infections such as cancer, AIDS, diabetes, bacterial infections, and nerve degeneration [12]. Muscle atrophy is also observed during aging, immobilization, and stress or trauma to the muscle and is associated with increased proteolysis. Protein degradation is essentially modulated by two conserved path‐ ways: the ATP-dependent ubiquitin-proteasome system and the autophagy pathways.

The first one has been particularly involved in the degradation process after the discovery of two E3 ubiquitin ligases (E3 ligases), MAFbx/atrogin-1 (muscle atrophy F-box) and MuRF1 (muscle RING finger-1), which are both overexpressed in various models of atrophy (fasting, cancer, diabetes, immobilization, and other stresses) [13,14]. The invalidation of these proteins confers a resistance to certain types of induced atrophy, suggesting a critical role in the catabolism for the ubiquitin-proteasome pathway [13]. The function of E3 ligases is to ubiq‐ uitinate specific proteins to target them for recognition by the 26S proteasome where they are eliminated. Other E3 ligases like zinc-finger protein 216 (ZNF216), the mitochondrial E3 ubiquitin protein ligase 1 (Mul1), and the tripartite motif-containing protein 32 (Trim32) have been shown to play an important role in skeletal muscle atrophy [15-17].

The autophagy signaling, which constitutes the second pathway, is important for maintain‐ ing cell metabolism and organelle turnover. It involves the degradation of substrates by hydrolases into a vesicle called lysosome [18]. Recent evidence demonstrates cross talk and cooperation between the ubiquitin-proteasome system and autophagy [19,20]. The impor‐ tance of this pathway in skeletal muscle was long much neglected, and autophagy was thought to be a nonselective degradation system. However, it is now well recognized that autophagy machineryis criticalformusclehomeostasisandorganelle turnoverinresponse tocellular stress like physical exercise or hypoxia [21]. Importantly, the energy sensor AMPK (5'-adenosine monophosphate-activated protein kinase) has been involved in the regulation of both protein translation pathway and protein degradation systems, with a particular interest in the regula‐ tion of autophagy program for the last few years. The present chapter focuses on the role of autophagy in skeletal muscle homeostasis. We will describe the functioning of the autophagy signaling pathways (i.e*.*, macroautophagy, microautophagy, and chaperone-mediated autophagy) and detail the regulation of macroautophagy by both AMPK and MTOR, with the final goal to discuss the potential applications of recent discoveries concerning autophagyrelated pathologies. The involvement of autophagy in response to physical exercise (acute and chronic exercise) and altitude exposure is thereafter discussed.
