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: 4.05). 05/2011; 43(9):1267-76. DOI: 10.1016/j.biocel.2011.05.007
Source: PubMed


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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    • "Despite substantial differences in circulating hormone levels between high and low exercise bouts, there was no difference in the increase in muscle fiber size and strength following training. Surprisingly, the mechanisms that underpin mechanical load-induced mTOR activation have remained largely elusive (Goodman 2014; Hornberger 2011). However , important work by Fang and colleagues (2001) proposed a mechanism of cell growth involving PA. "
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    ABSTRACT: Skeletal muscle mass plays a vital role in locomotion, whole-body metabolic health, and is a positive predictor of longevity. It is well established the mammalian target of rapamycin (mTOR) is a central regulator of skeletal muscle protein turnover. The pursuit to find novel nutrient compounds or functional food sources that possess the ability to activate mTOR and promote skeletal muscle protein accretion has been on going. Over the last decade, a key role has been proposed for the phospholipid phosphatidic acid (PA) in mTOR activation. Mechanical load-induced (i.e., resistance exercise) intramuscular PA can directly bind to and activate mTOR. In addition, PA provided exogenously in cell culture heightens mTOR activity, albeit indirectly. Thus, endogenously generated PA and exogenous provision of PA appear to act through distinct mechanisms that converge on mTOR and, potentially, may amplify muscle protein synthesis. In support of this notion, limited evidence from humans suggests that resistance exercise training combined with oral supplemental PA enhances strength gains and muscle hypertrophy. However, the precise mechanisms underpinning the augmented muscle remodelling response with supplemental PA remain elusive. In this review, we will critically examine available evidence from cell cultures and animal and human experimental models to provide an overview of the mechanisms through which endogenous and exogenous PA may act to promote muscle anabolism, and discuss the potential for PA as a therapeutic tool to maintain or restore skeletal muscle mass in the context of ageing and disease.
    Applied Physiology Nutrition and Metabolism 09/2015; 40(12). DOI:10.1139/apnm-2015-0350 · 2.34 Impact Factor
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    • "Although changes in the acute program variables surrounding a resistance exercise prescription have been suggested to promote differing anabolic responses and hypertrophic adaptation in skeletal muscle (Kraemer and Ratamess 2005), the optimal parameters of a resistance training program for regulating muscle growth remain unclear (Adams and Bamman 2012). The stimulus from muscle contraction during resistance exercise of differing intensities results in varying biochemical responses regulating the rate of protein synthesis (Hornberger 2011). At the cellular level, skeletal muscle adaptation is the result of the cumulative effects from transient changes in gene expression following acute bouts of exercise (Coffey and Hawley 2007). "
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    ABSTRACT: Resistance exercise paradigms are often divided into high volume (HV) or high intensity (HI) protocols, however, it is unknown whether these protocols differentially stimulate mTORC1 signaling. The purpose of this study was to examine mTORC1 signaling in conjunction with circulating hormone concentrations following a typical HV and HI lower-body resistance exercise protocol. Ten resistance-trained men (24.7 ± 3.4 years; 90.1 ± 11.3 kg; 176.0 ± 4.9 cm) performed each resistance exercise protocol in a random, counterbalanced order. Blood samples were obtained at baseline (BL), immediately (IP), 30 min (30P), 1 h (1H), 2 h (2H), and 5 h (5H) postexercise. Fine needle muscle biopsies were completed at BL, 1H, and 5H. Electromyography of the vastus lateralis was also recorded during each protocol. HV and HI produced a similar magnitude of muscle activation across sets. Myoglobin and lactate dehydrogenase concentrations were significantly greater following HI compared to HV (P = 0.01-0.02), whereas the lactate response was significantly higher following HV compared to HI (P = 0.003). The growth hormone, cortisol, and insulin responses were significantly greater following HV compared to HI (P = 0.0001-0.04). No significant differences between protocols were observed for the IGF-1 or testosterone response. Intramuscular anabolic signaling analysis revealed a significantly greater (P = 0.03) phosphorylation of IGF-1 receptor at 1H following HV compared to HI. Phosphorylation status of all other signaling proteins including mTOR, p70S6k, and RPS6 were not significantly different between trials. Despite significant differences in markers of muscle damage and the endocrine response following HV and HI, both protocols appeared to elicit similar mTORC1 activation in resistance-trained men. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
    07/2015; 3(7). DOI:10.14814/phy2.12466
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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.
    Journal of Muscle Research and Cell Motility 10/2013; 35(1). DOI:10.1007/s10974-013-9367-4 · 2.09 Impact Factor
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