Abstract
Skeletal muscle protein synthesis is a highly complex process, influenced by nutritional status, mechanical stimuli, repair programs, hormones, and growth factors. The molecular aspects of protein synthesis are centered around the mTORC1 complex. However, the intricacies of mTORC1 regulation, both up and downstream, have expanded overtime. Moreover, the plastic nature of skeletal muscle makes it a unique tissue, having to coordinate between temporal changes in myofiber metabolism and hypertrophy/atrophy stimuli within a tissue with considerable protein content. Skeletal muscle manages the push and pull between anabolic and catabolic pathways through key regulatory proteins to promote energy production in times of nutrient deprivation or activate anabolic pathways in times of nutrient availability and anabolic stimuli. Branched-chain amino acids (BCAAs) can be used for both energy production and signaling to induce protein synthesis. The metabolism of BCAAs occur in tandem with energetic and anabolic processes, converging at several points along their respective pathways. The fate of intramuscular BCAAs adds another layer of regulation, which has consequences to promote or inhibit muscle fiber protein anabolism. This review will outline the general mechanisms of muscle protein synthesis and describe how metabolic pathways can regulate this process. Lastly, we will discuss how BCAA availability and demand coordinate with synthesis mechanisms and identify key factors involved in intramuscular BCAA trafficking.
Highlights
Specialty section: This article was submitted to Signaling, a section of the journal Frontiers in Cell and Developmental
When eIF2 is phosphorylated, eIF2B is inhibited from recycling Guanosine diphosphate (GDP) back to Guanosine-5 -triphosphate (GTP) and translation is stopped (Rowlands et al, 1988). eIF2 is phosphorylated by several kinases including double stranded RNA-dependent protein kinase (PKR), heme-regulated inhibitor kinase (HRI), eukaryotic translation initiation factor 2-alpha kinase 3 (PERK), the yeast general control non-derepressible 2 (GCN2) (Proud, 2005), and more recently, glycogen synthase kinase-3 beta (GSK3β) (Welsh et al, 1998)
In C2C12 cells, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR)-induced AMP-activated kinase (AMPK) activation showed a reduction in protein synthesis, polysome aggregation and downstream mammalian target of rapamycin complex 1 (mTORC1) signaling proteins 4E-BP1, p70S6K and eEF2 (Williamson et al, 2006)
Summary
Protein synthesis is regulated primarily at the initiation phase of protein translation. A series of signaling proteins, referred to as eukaryotic initiation factors (eIFs), control this process and depend on upstream signals to modulate their activity. The binding of the methionyl tRNA (met-tRNA) to the 40S ribosomal subunit is regulated by the eukaryotic initiation factor 2 eIF2 (Price and Proud, 1994). EIF2 binds GTP and the eIF2-GTP-met-tRNA binds to the 40S ribosomal complex forming the 43S preinitiation complex. Once the start codon of an mRNA binds to the complex, GTP is hydrolyzed back to
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