Regulation of Protein Synthesis in Skeletal Muscle by Amino Acids: Role of mTORC1
Scot R. Kimball (Penn State College of Medicine)
Friday 12 October
“Regulation of Protein Synthesis in Skeletal Muscle by Amino Acids: Role of mTORC1,” Scot R. Kimball, Ph.D., Professor and Vice Chair of Research, Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, 11:15 am to 12:30 pm, 127 Noll Laboratory, host: Department of Kinesiology (865-7575).
Abstract: In a study reported more than 40 years ago, the branched-chain amino acids were shown to be as potent as a complete mixture of amino acids in stimulating protein synthesis in in vitro muscle preparations. That finding suggested that amino acids were not only substrates for protein synthesis, but that certain amino acids could also regulate the process. The question of how the branched-chain amino acids stimulate protein synthesis remained a mystery for 25 years, when my laboratory showed that the leucine-induced stimulation of muscle protein synthesis was blocked by rapamycin, an inhibitor of the protein kinase referred to as the mechanistic target of rapamycin in complex 1 (mTORC1). More recent studies have shown that leucine activates mTORC1 through a signaling pathway involving the Sestrin family of proteins. Specifically, leucine promotes Sestrin2 dephosphorylation and dissociation from a protein complex referred to as GATOR2 that leads to activation of the Ras-related GTP binding (Rag) proteins and subsequently, activation of mTORC1. Moreover, we have shown that leucine acts in a synergistic manner with hormones such as insulin or insulin-like growth factor 1 (IGF-1) to activate mTORC1. However, in contrast to leucine, hormone-induced mTORC1 activation occurs through a Rag-independent signaling pathway involving Akt-mediated activation of the Ras homolog enriched in brain (Rheb). Thus, expression of either constitutively active (ca) Rags or caRheb partially activates mTORC1, but co-expression of caRags and caRheb leads to a significantly greater activation compared to expression of either one alone. In contrast, activation of mTORC1 is attenuated by a stress-induced protein referred to as regulated in development and DNA damage responses 1 (REDD1). For example, glucocorticoids potently upregulate REDD1 expression in skeletal muscle in association with repressed rates of protein synthesis and mTORC1 activity. Consequently, conditions associated with enhanced circulating glucocorticoid concentrations such as fasting, type 1 diabetes, and mental stress, attenuate the mTORC1 activation normally induced by anabolic stimuli, e.g. feeding and muscle contraction. Notably, in mice lacking REDD1, muscle protein synthesis and mTORC1 activity are elevated compared to wild-type mice, and the effect of anabolic stimuli is enhanced.