Integration of signals generated by nutrients, hormones, and exercise in skeletal muscle

Abstract

This review focuses on anabolic signaling pathways through which insulin, amino acids, and resistance exercise act to regulate the protein kinase complex referred to as mechanistic target of rapamycin complex (mTORC) 1. Initially, individual pathways through which the 3 anabolic signals act to modulate mTORC1 signaling will be discussed, followed by a summation of evidence showing an additive effect of the regulators. The emphasis will be on mTORC1 signaling in skeletal muscle and its contribution to modulation of rates of protein synthesis. In addition, results from studies using cells in culture will be used to provide a more complete picture of the molecular details of the individual pathways.

FIGURE 1.

Signaling pathways that modulate amino acid, insulin/IGF-I, and resistance exercise–induced activation of mTORC1 signaling. Hormones such as insulin and IGF-I signal to mTORC1 through Akt- and ERK1/2-dependent inactivation of TSC1/2 GAP activity, leading to enhanced GTP-loading of Rheb at late endosomal/lysosomal membranes. Amino acids promote GTP loading of RagA/B by both inhibiting Ragulator GAP activity and stimulating GATOR GEF activity. Ragulator also acts to localize the Rag complex to the late endosomal/lysosomal membrane. The binding of mTORC1 to the Rag complex allows it to interact with Rheb-GTP and become active. The signaling pathway or pathways through which resistance exercise acts to stimulate mTORC1 signaling is less clear, with Akt, ERK, and phosphatidic acid all playing possible roles. c7orf59, chromosome 7 open reading frame 59; ERK, extracellular-regulated protein kinase; GAP, GTPase activator protein; GATOR, GAP activity toward Rags; GEF, guanine nucleotide exchange factor; IGF-I, insulin-like growth factor I; mLST8, lethal with SEC13 protein 8; mTOR, mechanistic target of rapamycin; mTORC, mTOR complex; Rag, Ras-related GTP binding; raptor, regulatory-associated protein of mTOR, complex 1; Rheb, ras homolog enriched in brain; Sec13, secretory 13; TBC1D7, ubiquitin specific peptide 6 (Trc-2)/budding uninhibited by benzimidazole/cell division cycle; TSC, tuberous sclerosis complex.

FIGURE 2.

mTORC1 interacts with Rheb and Rag GTPases at the late endosomal/lysosomal membrane. The Ragulator complex is anchored to late endosomal/lysosomal membranes through p18, which is myristoylated and palmitoylated (12). The RagA/B-RagC/D complex binds to Ragulator, and when RagA/B is associated with GTP, it also binds to mTORC1 to recruit it to the membrane where it interacts with Rheb. Rheb is also subject to lipid modification (farnesylation), leading to its localization to intracellular membranes (reviewed in reference 45). The results of studies assessing TSC1/2 subcellular distribution have been inconsistent. However, a portion of the complex has been shown to interact with subcellular membranes (46). It seems likely that TSC1/2 interfaces with Rheb at the late endosomal/lysosomal membrane. c7orf59, chromosome 7 open reading frame 59; IGF-I, insulin-like growth factor I; mLST8, lethal with SEC13 protein 8; mTOR, mechanistic target of rapamycin; mTORC, mTOR complex; Rag, Ras-related GTP binding; raptor, regulatory-associated protein of mTOR, complex 1; Rheb, ras homolog enriched in brain; TBC1D7, ubiquitin specific peptide 6 (Trc-2)/budding uninhibited by benzimidazole/cell division cycle; TSC, tuberous sclerosis complex.