Figure 1.

Metabolite-dependent mechanisms that influence muscle fiber composition. (A) The mTORC1 signal transduction pathway is controlled by amino acid-, growth factor- and energy-dependent signaling mechanisms. Amino acid-dependent signaling through Sestrin, CASTOR, and SAMTOR, repress GATOR2-dependent inhibition of GATOR1 GAP activity toward Rag GTP-binding proteins. Growth factor signaling through the phosphatidylinositol 3 kinase (PI3K): AKT pathway inhibits the GAP activity of the tuberous sclerosis complex (TSC) toward Rheb. These pathways lead to the stimulation of mTORC1 activity. Cellular energy status controls mTORC1 through a regulatory loop between the growth factor signaling pathway and the sensor of AMP called AMPK. Downstream targets of mTORC1 control protein translation and metabolic pathways that provide the substrates required for growth. (B) Ligand activation of nuclear hormone receptors (NHRs), including PPARδ and TRα, and form a heterodimer with retinoic acid receptor (RXR) that recruits coactivator proteins to the nuclear hormone response elements (NHRE) of the promoters of genes involved in mitochondrial gene expression and skeletal muscle fiber-type switching.