Several studies have established that signaling through mTOR is necessary for growth of adult skeletal muscle. The general objective of the parent grant (AR45617) is to define the molecular mechanisms whereby mechanical events and growth factors mediate the intracellular activation of mTOR signaling and protein synthesis during skeletal muscle hypertrophy. The experiments described in this competitive revision will expand the scope of the work proposed in the parent grant with the pursuit of the role of REDD2/ddit4l, a novel negative regulator of mTOR/TORC1 signaling. The overall hypothesis is that targeted disruption of REDD2 expression in adult skeleletal muscle will result in increased mTOR activity, increased protein synthesis and greater growth. Expression of REDD2 is highly and uniquely enriched in adult skeletal muscle in mice, rats and humans. Recent experiments in my lab have determined that expression of REDD2 is quickly and significantly down-regulated in both human and mouse muscle in response to hypertrophic stimuli. Using in vitro approaches we have also determined that REDD2 functions as a negative regulator of mTOR signaling in muscle cells. These new observations expand the scope of our current project on mTOR signaling and skeletal muscle. In addition they suggest that REDD2 may play a critical role in modulating the signaling activity through mTOR with downstream effects on protein synthesis and skeletal muscle hypertrophy. To address the hypothesis of this competitive revision we propose the following two specific aims:
Specific Aim 1. To determine the molecular mechanism(s) by which REDD2 inihibits mTOR/TORC1 signaling in response to mechanical strain in myotubes in vitro.
Specific Aim 2. To determine the role of loss of function of REDD2 in adult skeletal muscle, in vivo, on mTOR/TORC1 signaling, rates of protein synthesis and muscle size. The objectives of this competitive revision are consistent with the goals of the announcement NOT-OD-09-058 and are three-fold. Our first objective is to expand our current research program (AR45617) with studies on the role of REDD2 in the regulation of skeletal muscle signaling during hypertrophy. The second objective is to hire new personnel to accomplish the research goal and third is to invest in the generation of a new mouse model, floxed REDD2, that is essential for this work and will contribute to the field of skeletal muscle research.
The goals of this project are to pursue our understanding of a novel skeletal muscle specific molecule, REDD2, which contributes to the regulation of growth/anabolic pathways in adult skeletal muscle. The results from these studies provide novel insight, and potentially a new target molecule, for pursuing therapeutic strategies to facilitate muscle growth and/or attenuate muscle wasting associated with disuse, aging, bed rest and cachexia.
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|Chaillou, Thomas; Lee, Jonah D; England, Jonathan H et al. (2013) Time course of gene expression during mouse skeletal muscle hypertrophy. J Appl Physiol (1985) 115:1065-74|
|Srikuea, Ratchakrit; Zhang, Xiping; Park-Sarge, Ok-Kyong et al. (2012) VDR and CYP27B1 are expressed in C2C12 cells and regenerating skeletal muscle: potential role in suppression of myoblast proliferation. Am J Physiol Cell Physiol 303:C396-405|
|McCarthy, John J; Mula, Jyothi; Miyazaki, Mitsunori et al. (2011) Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development 138:3657-66|
|Drummond, Micah J; McCarthy, John J; Sinha, Mala et al. (2011) Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis. Physiol Genomics 43:595-603|
|Miyazaki, Mitsunori; McCarthy, John J; Fedele, Mark J et al. (2011) Early activation of mTORC1 signalling in response to mechanical overload is independent of phosphoinositide 3-kinase/Akt signalling. J Physiol 589:1831-46|
|Mavalli, Mahendra D; DiGirolamo, Douglas J; Fan, Yong et al. (2010) Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice. J Clin Invest 120:4007-20|
|McCarthy, John J; Esser, Karyn A (2010) Anabolic and catabolic pathways regulating skeletal muscle mass. Curr Opin Clin Nutr Metab Care 13:230-5|
|Esser, Karyn A; McCarthy, John J; Miyazaki, Mitsunori (2010) Comments on Point:Counterpoint: IGF is/is not the major physiological regulator of muscle mass. IGF-1 is not key for adult skeletal muscle hypertrophy. J Appl Physiol 108:1830|
|Miyazaki, Mitsunori; McCarthy, John J; Esser, Karyn A (2010) Insulin like growth factor-1-induced phosphorylation and altered distribution of tuberous sclerosis complex (TSC)1/TSC2 in C2C12 myotubes. FEBS J 277:2180-91|
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