Involvement of PI3K/Akt/TOR pathway in stretch‐induced hypertrophy of myotubes

Abstract

Skeletal muscle cells are hypertrophied by mechanical stresses, but the underlying molecular mechanisms are not fully understood. Two signaling pathways, phosphatidylinositol 3-kinase (PI3K)/Akt to target of rapamycin (TOR) and extracellular signal-regulated kinase kinase (MEK) to extracellular signal-regulated kinase (ERK), have been proposed to be involved in muscle hypertrophy. In this study we examined the involvement of these pathways in primary cultures of chick skeletal myotubes subjected to passive cyclic stretching for 72 hours, a time that was sufficient to induce significant hypertrophy in our preparations. Hypertrophy was largely suppressed by wortmannin or rapamycin, inhibitors of PI3K or mTOR, respectively. Furthermore, phosphorylation of Akt was enhanced by stretching and suppressed by wortmannin. The MEK inhibitor, U0126, exerted a minimal influence on stretch-induced hypertrophy. We found that cyclic stretching of myotubes activates the PI3K/Akt/TOR pathway, resulting in muscle hypertrophy. The MEK/ERK pathway may contribute negatively to spontaneous hypertrophy.

Intramuscular MAPK signaling following high volume and high intensity resistance exercise protocols in trained men

“…Among the intramuscular signaling networks, mTORC1 appears to be the primary regulator of muscle protein synthesis and growth (Goodman 2014). Although MAPK signaling may promote activation of mTORC1 signaling, MAPK signaling does not appear to be absolutely necessary for mechanically induced mTORC1 activation (Sasai et al 2010;You et al 2012). It remains unclear whether maximal stimulation of muscle protein synthesis is mediated by the convergence of mTORC1 and MAPK signaling pathways on downstream targets, such as p70S6 kinase (p70S6k) and ribosomal protein S6 (RPS6).…”

Mechanical Stretch Up-regulates MicroRNA-26a and Induces Human Airway Smooth Muscle Hypertrophy by Suppressing Glycogen Synthase Kinase-3β

“…The best characterized system responses to mechanical stimuli are the cardiovascular (17-21), musculoskeletal (22)(23)(24), and pulmonary physiology (25,(33)(34)(35)(36)(37)(38) changes to airway smooth muscle, due to hypertrophy and/or hyperplasia, are a well known feature of chronic airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis (12)(13)(14)(15)(16). Alterations in the regulation of gene expression by mechanical stimuli play an important role in the thickening and remodeling of the airway wall in subjects with the above airway diseases (25).…”

“…Clinical studies have shown that both hypertrophy and hyperplasia of human airway smooth muscle cells (HASMCs) play key roles in airway remodeling (12)(13)(14)(15)(16). Many lines of evidence have demonstrated that hypertrophy in cardiomyocytes, skeletal myotubes, and smooth muscle cells is induced by various hypertrophic stimuli, including mechanical stretch (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Recently, it has been shown that miRNAs play important roles in the induction of cardiac hypertrophy as well as response to hypertrophic stimuli (28 -32).…”

“…Stretch Induces HASMCs Hypertrophy-Accumulating evidences have demonstrated that stretch can induce cardiac, skeletal, and smooth muscle cell hypertrophy (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). To test this in HASMCs, we stimulated the cells with a 1-h stretch for every 12 h up to 3 days.…”

Body weight-dependent troponin T alternative splicing is evolutionarily conserved from insects to mammals and is partially impaired in skeletal muscle of obese rats

“…It is becoming apparent that many alternative splicing events require the activity of the same signaling pathways (Lynch, 2007). For example, the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR (mammalian target of rapamycin) signaling cascade mediates skeletal muscle protein synthesis in response to nutritional and mechanical stimuli (Anthony et al, 2000;Bolster et al, 2003;Kimball and Jefferson, 2006;Kimball et al, 2000;Sasai et al, 2010), and also activates and interacts with members of the serine/arginine (SR)-rich protein family (Blaustein et al, 2009;Karni et al, 2008;Lynch, 2007), a ubiquitous set of alternative splicing factors that affect exon inclusion/exclusion and facilitate translation of specific mRNAs (Blaustein et al, 2005;Sanford et al, 2005). Modulation of sarcomere gene alternative splicing by nutritional and/or mechanically induced signaling through PI3K/Akt/mTOR would add important functionality to the already complex nature of this pathway, and may mediate the dietary and weight-loading effects on troponin T alternative splicing observed in both insects and mammals.…”