In skeletal muscle, protein levels are determined by relative rates of protein synthesis and breakdown. The balance between synthesis and degradation of intracellular components determines the overall muscle fiber size. AMP-activated protein kinase (AMPK), a sensor of cellular energy status, was recently shown to increase myofibrillar protein degradation through the expression of MAFbx and MuRF1. In the present study, the effect of AMPK activation by AICAR on autophagy was investigated in muscle cells. Our results show that FoxO3a transcription factor activation by AMPK induces the expression of the autophagy-related proteins LC3B-II, Gabarapl1, and Beclin1 in primary mouse skeletal muscle myotubes and in the Tibialis anterior (TA) muscle. Time course studies reveal that AMPK activation by AICAR leads to a transient nuclear relocalization of FoxO3a followed by an increase of its cytosolic level. Moreover, AMPK activation leads to the inhibition of mTORC1 and its subsequent dissociation of Ulk1, Atg13, and FIP200 complex. Interestingly, we identify Ulk1 as a new interacting partner of AMPK in muscle cells and we show that Ulk1 is associated with AMPK under normal conditions and dissociates from AMPK during autophagy process. Moreover, we find that AMPK phosphorylates FoxO3a and Ulk1. In conclusion, our data show that AMPK activation stimulates autophagy in skeletal muscle cells through its effects on the transcriptional function of FoxO3a and takes part in the initiation of autophagosome formation by interacting with Ulk1. Here, we present new evidences that AMPK plays a crucial role in the fine tuning of protein expression programs that control skeletal muscle mass.

The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.

The eukaryotic initiation factor 3 subunit f (eIF3f) is one of the 13 subunits of the translation initiation factor complex eIF3 required for several steps in the initiation of mRNA translation. In skeletal muscle, recent studies have demonstrated that eIF3f plays a central role in skeletal muscle size maintenance. Accordingly, eIF3f overexpression results in hypertrophy through modulation of protein synthesis via the mTORC1 pathway. Importantly, eIF3f was described as a target of the E3 ubiquitin ligase MAFbx/atrogin-1 for proteasome-mediated breakdown under atrophic conditions. The biological importance of the MAFbx/atrogin-1-dependent targeting of eFI3f is highlighted by the finding that expression of an eIF3f mutant insensitive to MAFbx/atrogin-1 polyubiquitination is associated with enhanced protection against starvation-induced muscle atrophy. A better understanding of the precise role of this subunit should lead to the development of new therapeutic approaches to prevent or limit muscle wasting that prevails in numerous physiological and pathological states such as immobilization, aging, denervated conditions, neuromuscular diseases, AIDS, cancer, diabetes. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Key points In muscular cells, eukaryotic initiation factor subunit f (eIF3f) activates protein synthesis by allowing physical interaction between mechanistic target of rapamycin complex 1 (MTORC1) and ribosomal protein S6 kinase 1 (S6K1), although its physiological role in animals is unknown. A knockout approach suggests that homozygous mice carrying a null mutation of the eIF3f gene fail to develop and consequently die at early embryonic stage, whereas heterozygous mice associated with a partial depletion of eIF3f gene grow normally and are phenotypically indistinguishable from wild‐type mice. Heterozygous mice express reduced eIF3f mRNA and protein levels in skeletal muscles and show diminished muscle mass associated with a decrease in the protein synthesis rate and an inhibition of the MTORC1 pathway. During hindlimb immobilization, heterozygous eIF3f mice display an exacerbated immobilization‐induced muscle atrophy associated with reduced protein synthesis. These results highlight the essential role of eIF3f during embryonic development and its involvement in muscular homeostasis via protein synthesis regulation. Abstract Eukaryotic translation initiation factor 3, subunit F (eIF3f), a component of eIF3 complex, plays an important role in protein synthesis regulation, although its physiological functions are unknown. We generated and analysed mice carrying a null mutation in the eIF3f gene. We showed that homozygous eIF3f knockout fail to develop and that eIF3f−/− embryos die at an early stage of development but after the pre‐implantation stage. However, disrupting one eIF3f allele does not affect growth, viability and fertility of heterozygous mice but, instead, reduces eIF3f mRNA and protein levels in all tissues examined. Although heterozygous mice are phenotypically indistinguishable from wild‐type mice, they present a diminished body weight and a lean mass reduction associated with normal body size. Interestingly, skeletal muscles are mainly affected and display an altered cell size without modification of fibre number. Skeletal muscles of heterozygous mice show a deficiency in polysome content, a decrease in protein synthesis rate and an inhibition of the mechanistic target of rapamycin (MTOR) pathway. We then studied the effects of hindlimb immobilization that mimic muscle disuse on heterozygous mice aiming to further explore the involvement of eIF3f in protein synthesis. We found that eIF3f partial depletion amplifies muscle atrophy compared to wild‐type mice. Mass and cross‐sectional area decreases were associated with reduced MTOR pathway activation and protein synthesis rate. Taken together, our data indicate that eIF3f is essential for mice embryonic development and controls adult skeletal muscle mass via protein synthesis regulation in a MTOR‐dependent manner.

Abstract"utophagy 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."utophagy 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 monophosphate "MP -activated protein kinase "MPK and the mechanistic target of rapamycin MTOR . "MPK acts as a sensor of cellular energy status by regulating several intracellular systems including glucose and lipid metabolisms and mitochondrial biogenesis. Recently, "MPK has been involved in the control of protein synthesis by decreasing MTOR activity and in the control of protein breakdown programs.Concerning proteolysis, "MPK notably regulates autophagy through FoxO transcription factors and Ulk 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. . IntroductionSkeletal 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 [ ].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 MTORC , a multiprotein complex composed of MTOR mammalian/mechanistic target of rapamycin , RPTOR regulatory-associated protein of MTOR , mLST /G L MTOR-associated protein LST homolog , DEPTOR DEP domain containing MTOR-interacting protein , and PR"S proline-ri...