Proposed model for the signaling pathways mediating fiber type transformation, mitochondrial biogenesis, and GLUT4 protein expression with skeletal muscle adaptations to endurance training. Exercise training leads to skeletal muscle fiber type transformation, mitochondrial biogenesis, and increased glucose transporter 4 (GLUT4) protein expression, and multiple signaling pathways have been suggested to be involved in these adaptations. Changes in the cellular energy status (AMP:ATP) stimulate AMP-activated protein kinase in the presence of the AMPK kinase, LKB1. AMPK may be involved in fiber type transformation, mitochondrial biogenesis, and GLUT4 biogenesis through increasing peroxisome-proliferator-activated receptor-γ coactivator 1α (PGC-1α) expression and probably also independent of PGC-1α. Exercise training-induced increases in PGC-1α are potentiated by a positive feedback loop through myocyte-enhancing factor 2 (MEF2) and are involved in fiber type transformation, mitochondrial biogenesis, and increased GLUT4 expression. Increases in intracellular Ca²⁺ levels lead to activation of the Ca²⁺/calmodulin-dependent phosphatase, calcineurin, as well as Ca²⁺/calmodulin-dependent protein kinases (CaMKs). While calcineurin is involved in a number of skeletal muscle adaptations, acting primarily through PGC-1α, a role of CaMKs has so far pointed toward increasing GLUT4 protein expression. Contraction-induced activation of p38 mitogen activated protein kinase (p38 MAPK) increases PGC-1α expression through activating transcription factor 2 (ATF2) and may therefore also be involved in skeletal muscle adaptations to exercise training.

Proposed model for the signaling pathways mediating insulin and contraction-induced skeletal muscle glucose transport. Insulin and contraction-mediated glucose transport occurs by translocation of glucose transporter 4 (GLUT4) from intracellular locations to the plasma membrane. Insulin binding leads to phosphorylation of the insulin receptor with subsequent activation of insulin receptor substrate 1/2 (IRS-1/2) and phosphatidylinositol 3-kinase (PI3-kinase). Downstream of PI3-kinase the protein kinases, Akt, which then regulates activation of Akt Substrate of 160 kD (AS160), and atypical protein kinase C (aPKC), have been identified to mediate insulin stimulated GLUT4 translocation. Contraction stimulated glucose uptake is mediated by multiple signaling pathways including aPKC, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK), LKB1, and AMP-activated protein kinase (AMPK).