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. 2023 Jun 30;27(2):78–95. doi: 10.20463/pan.2023.0021

Figure 1.

Figure 1.

Schematic representation of the coupling between sarcomeric force development during contraction and the associated molecular signaling which controls gene expression, protein synthesis and degradation. (1) Sarcomeric contraction initiates force development that is laterally transduced via the sarcomeric cytoskeleton. Titin, a giant spring-like sarcomeric protein, senses mechanical forces and contributes to skeletal muscle adaptation by altering molecular signaling pathways. (2) Force transmission via integrins and the dystrophin-glycoprotein complex to the extracellular matrix (ECM). Mechanical stimulation of the sarcomeric environment activates mTOR (mammalian target of rapamycin)- signaling independently of AKT (protein kinase B). (3) Mechanical stimulation via contraction activates PLD (phospholipase D), generating phosphatidic acid, which activates mTOR signaling. (4) Growth factors like Insulin-like growth factor 1 (IGF-1) mediate the AKT-dependent activation of mTOR. (5) Leucine availability activates mTOR independent of growth factors. (6) Force-sensing integrins mediate focal adhesion kinase (FAK)-activation, which can activate p70S6K (70-kDa ribosomal protein S6 kinase) independent of mTOR. Additionally, MAP kinases activate p90S6K (90-kDa ribosomal protein S6 kinase), which phosphorylates rpS6 also independently of mTOR. (7) Protein synthesis (8) is predominantly activated by mTOR; however, other signaling components converge and control translation initiation. Activated mTOR (mTORC1/2 complex) controls protein synthesis by phosphorylating 4E-BP1 (4E-binding protein 1), relieving its inhibitory effect on eiF4E; mTOR further phosphorylates p70S6K, which phosphorylates and activates rpS6 (ribosomal protein S6). AKT activation phosphorylates and inhibits glycogen synthase kinase 3 (GSK3)-beta and relieves its inhibitory effect on eiF2B, which is required for translational regulation. (9) Molecular signaling kinases, e.g., mitogen-activated protein kinase (MAPK), AKT and adenosine monophosphate-activated protein kinase (AMPK), activate transcription factors, which enter the nucleus to initiate gene expression (red arrows). (10) Metabolic stress induced by increased adenosine triphosphate (ATP) turnover activates AMPK, which phosphorylates tuberous sclerosis complex 2 (TSC2) proteins that inhibit mTOR activity. (11) Forkhead-box (FOXO) proteins control the expression of muscle RING-finger 1 (MuRF-1) and muscle atrophy-F-box/ atrogin1 (MAFbx) proteins, and E3 ligases, which control the degradation of sarcomeric proteins via proteasomal degradation. (12) Growth factor signaling via insulin or IGF-1 phosphorylates and activates AKT, which inhibits FOXO proteins via phosphorylation and by that proteasomal degradation of sarcomeric proteins.