Molecular regulation of human skeletal muscle protein synthesis in response to exercise and nutrients: a compass for overcoming age-related anabolic resistance

Abstract

Skeletal muscle mass, a strong predictor of longevity and health in humans, is determined by the balance of two cellular processes, muscle protein synthesis (MPS) and muscle protein breakdown. MPS seems to be particularly sensitive to changes in mechanical load and/or nutritional status; therefore, much research has focused on understanding the molecular mechanisms that underpin this cellular process. Furthermore, older individuals display an attenuated MPS response to anabolic stimuli, termed anabolic resistance, which has a negative impact on muscle mass and function, as well as quality of life. Therefore, an understanding of which, if any, molecular mechanisms contribute to anabolic resistance of MPS is of vital importance in formulation of therapeutic interventions for such populations. This review summarizes the current knowledge of the mechanisms that underpin MPS, which are broadly divided into mechanistic target of rapamycin complex 1 (mTORC1)-dependent, mTORC1-independent, and ribosomal biogenesis-related, and describes the evidence that shows how they are regulated by anabolic stimuli (exercise and/or nutrition) in healthy human skeletal muscle. This review also summarizes evidence regarding which of these mechanisms may be implicated in age-related skeletal muscle anabolic resistance and provides recommendations for future avenues of research that can expand our knowledge of this area.

Keywords: ERK1/2; anabolic resistance; mTORC1; muscle protein synthesis.

Fig. 1.

Schematic illustration of mRNA translation into protein. After transcription of a new strand of mRNA in the nucleus, this mRNA strand will undergo splicing and then be transported to the cytosol, where eukaryotic initiation factor (eIF) 4E will bind to its 5′-end and allow formation of the preinitiation complex (eIF4G, eIF4A, and eIF4B). This complex will unwind the secondary structure of the mRNA strand, “priming” it for translation. Next, the 40S subunit, complexed with eIF2-guanosine triphosphate (GTP), and a transfer RNA (tRNA), loaded with methionine (eIF2-GTP-Met-tRNA), is recruited, forming the 43S initiation complex, which recognizes the start codon (AUG) on the mRNA strand. Upon arrival at the start codon, this complex of initiation factors is released, and the large (60S) ribosomal subunit binds with the 40S subunit to form the full 80S subunit needed for translation. The 60S subunit recognizes each codon and recruits the corresponding loaded tRNA. The catalytic activity of the rRNA then forms a peptide bond between 2 amino acids (AAs), and the ribosome moves to the next codon, while the now-empty tRNA is released to the cytoplasm to bind with another AA. This process, aided by translation elongation factors, continues to occur along the entire mRNA strand until the ribosome hits a stop codon. Here, a release factor, which aids release of the newly formed peptide chain from the ribosome, is recruited. This peptide chain then undergoes various folding steps to achieve full functionality.

Fig. 2.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent regulation of protein translation. Once activated, mTORC1 phosphorylates several downstream targets that regulate protein translation. The first is ribosomal protein S6 kinase 1 (S6K1), which is phosphorylated at Thr³⁸⁹ by mTORC1. This kinase phosphorylates its downstream targets, eukaryotic elongation factor (eEF) 2K (eEF2K), ribosomal protein S6 (rpS6), eukaryotic initiation factor (eIF) 4B (eIF4B), and upstream binding factor (UBF), which cause an elevation of translation initiation (eIF4B), translation elongation (eEF2K), and rRNA transcription (UBF). A second direct mTORC1 target is eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which is phosphorylated and inhibited by the kinase complex. 4EBP1 is then removed from its association with eIF4E and allows the preinitiation complex to bind with the 5′ cap of the mRNA strand. mTORC1 also directly phosphorylates eIF4G on several residues in a further mechanism to enhance translation initiation. P, phosphorylation; RAPTOR, regulatory-associated protein of mTOR; PRAS40, proline-rich AKT substrate of 40 kDa; DEPTOR, DEP domain-containing mTOR-interacting protein; GβL, mammalian lethal with SEC13 protein 8/G protein β-subunit-like.

Fig. 3.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-independent regulation of protein translation. The majority of mTORC1-independent mechanisms governing protein translation occur via the MAPK/ERK1/2 pathway. This pathway begins at the cell membrane with activation of Ras kinases via conversion of GDP to GTP. These RAS proteins then initiate a signaling cascade, culminating in phosphorylation and activation of ERK1/2, which will phosphorylate several downstream targets, the most predominant of which is p90 ribosomal protein S6 kinase (p90RSK). This kinase phosphorylates a set of substrates similar to ribosomal protein S6 kinase 1 (S6K1). ERK1/2 will also phosphorylate MAP kinase-interacting kinase 1 (MNK1), which elevates translation initiation through phosphorylation of eukaryotic initiation factor (eIF) 4G and eIF4E. rRNA transcription is also elevated in an ERK1/2-dependent fashion via phosphorylation of c-myc and upstream binding factor (UBF). Finally, ERK1/2 signaling may affect mTORC1 activation through phosphorylation of tuberous sclerosis complex 2 (TSC2), which is removed from mTORC1’s direct activator Rheb. eEF, eukaryotic elongation factor; FAK, focal adhesion kinase; P, phosphorylation; RAPTOR, regulatory-associated protein of mTOR; PRAS40, proline-rich AKT substrate of 40 kDa; DEPTOR, DEP domain-containing mTOR-interacting protein; GβL, mammalian lethal with SEC13 protein 8/G protein β-subunit-like.