Article

Mechanotransduction and the regulation of mTORC1 signaling in skeletal muscle

Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706, USA.
The international journal of biochemistry & cell biology (Impact Factor: 4.24). 05/2011; 43(9):1267-76. DOI: 10.1016/j.biocel.2011.05.007
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ABSTRACT Mechanical stimuli play a major role in the regulation of skeletal muscle mass, and the maintenance of muscle mass contributes significantly to disease prevention and issues associated with the quality of life. Although the link between mechanical signals and the regulation of muscle mass has been recognized for decades, the mechanisms involved in converting mechanical information into the molecular events that control this process remain poorly defined. Nevertheless, our knowledge of these mechanisms is advancing and recent studies have revealed that signaling through a protein kinase called the mammalian target of rapamycin (mTOR) plays a central role in this event. In this review we will, (1) discuss the evidence which implicates mTOR in the mechanical regulation of skeletal muscle mass, (2) provide an overview of the mechanisms through which signaling by mTOR can be regulated, and (3) summarize our current knowledge of the potential mechanisms involved in the mechanical activation of mTOR signaling.

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Available from: Troy A Hornberger, Jul 28, 2015
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    • "Rheb and PA: the direct activators of mTOR It is well recognized that mTOR can sense and respond to a very wide range of different stimuli, but surprisingly, only two molecules have been shown to function as direct activators of mTOR signaling (Sengupta et al. 2010; Hornberger 2011). These molecules include the lipid second messenger PA and the Ras-related GTPase Rheb. "
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    ABSTRACT: It is well recognized that mechanical signals play a critical role in the regulation of skeletal muscle mass, and the maintenance of muscle mass is essential for mobility, disease prevention and quality of life. Furthermore, over the last 15 years it has become established that signaling through a protein kinase called the mammalian (or mechanistic) target of rapamycin (mTOR) is essential for mechanically-induced changes in protein synthesis and muscle mass, however, the mechanism(s) via which mechanical stimuli regulate mTOR signaling have not been defined. Nonetheless, advancements are being made, and an emerging body of evidence suggests that the late endosome/lysosomal (LEL) system might play a key role in this process. Therefore, the purpose of this review is to summarize this body of evidence. Specifically, we will first explain why the Ras homologue enriched in brain (Rheb) and phosphatidic acid (PA) are considered to be direct activators of mTOR signaling. We will then describe the process of endocytosis and its involvement in the formation of LEL structures, as well as the evidence which indicates that mTOR and its direct activators (Rheb and PA) are all enriched at the LEL. Finally, we will summarize the evidence that has implicated the LEL in the regulation of mTOR by various growth regulatory inputs such as amino acids, growth factors and mechanical stimuli.
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    • "To adress the reflections of Dr. Yamada, unlike previous human exercise studies, our approach did in fact provide support for the hypothesis that Akt-independent mTORC1 signaling is switched on selectively by the mechanical strain inherent of heavy load resistance exercise (involving both eccentric and concentric modality), but not moderate intensity endurance exercise (Vissing et al., 2011). Also according to an AMPK-mTORC1 switch hypothesis, our endurance exercise protocol switched on AMPK signaling and with reference to previous investigations, it is likely that AMPK simultaneously switched off mTORC1 signaling through TSC2 or raptor (Goodman et al., 2011; Hornberger, T., 2011). The very modest degree of AMPK activation after resistance exercise (which was not statistically different from endurance exercise), imply that exercise and post-exercise metabolic demands after resistance exercise can actually be substantial enough to switch on AMPK signaling. "
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    ABSTRACT: The maintenance of muscle mass is critical for health and issues associated with the quality of life. Over the last decade, extensive progress has been made with regard to our understanding of the molecules that regulate skeletal muscle mass. Not surprisingly, many of these molecules are intimately involved in the regulation of protein synthesis and protein degradation [e.g. the mammalian target of rapamycin (mTOR), eukaryotic initiation factor 2B (eIF2B), eukaryotic initiation factor 3f (eIF3f) and the forkhead box O (FoxO) transcription factors]. It is also becoming apparent that molecules which sense, or control, the energetic status of the cell play a key role in the regulation of muscle mass [e.g. AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC1α)]. In this review we will attempt to summarize the current knowledge of how these molecules regulate skeletal muscle mass.
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