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
Source: PubMed

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.

Download full-text

Full-text

Available from: Troy A Hornberger, Aug 29, 2015
2 Followers
 · 
119 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 1.93 Impact Factor
  • Source
    • "Although BCAAs are required for mTORC1-dependent muscle protein synthesis [20,21], BCAA intake alone is not sufficient to significantly increase muscle mass. Mechanical stimuli, which activate mTORC1 in myocytes, are of critical importance to cause significant skeletal muscle hypertrophy [22,23] (Figure  1B). Intriguingly, eccentric muscle contractions increase mTORC1 activation by phosphorylation of tuberous sclerosis complex-2 (TSC2) associated with the translocation of TSC2 away from the lysosome [24]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Milk protein intake has recently been suggested to improve metabolic health. This Perspective provides evidence that metabolic effects of milk protein intake have to be regarded in the context of the individual's pre-existing metabolic and exercise status. Milk proteins provide abundant branched-chain amino acids (BCAAs) and glutamine. Plasma BCAAs and glutamine are increased in obesity and insulin resistance, but decrease after gastric bypass surgery resulting in weight loss and improved insulin sensitivity. Milk protein consumption results in postprandial hyperinsulinemia in obese subjects, increases body weight of overweight adolescents and may thus deteriorate pre-existing metabolic disturbances of obese, insulin resistant individuals.
    Nutrition & Metabolism 10/2013; 10(1):60. DOI:10.1186/1743-7075-10-60 · 3.36 Impact Factor
Show more