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Review
. 2008 Mar;60(3):145-53.
doi: 10.1002/iub.21.

Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise

Katja S C Röckl  1 , Carol A Witczak, Laurie J Goodyear
Affiliations
Review

Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise

Katja S C Röckl et al. IUBMB Life. 2008 Mar.

Abstract

Physical activity elicits physiological responses in skeletal muscle that result in a number of health benefits, in particular in disease states, such as type 2 diabetes. An acute bout of exercise/muscle contraction improves glucose homeostasis by increasing skeletal muscle glucose uptake, while chronic exercise training induces alterations in the expression of metabolic genes, such as those involved in muscle fiber type, mitochondrial biogenesis, or glucose transporter 4 (GLUT4) protein levels. A primary goal of exercise research is to elucidate the mechanisms that regulate these important metabolic and transcriptional events in skeletal muscle. In this review, we briefly summarize the current literature describing the molecular signals underlying skeletal muscle responses to acute and chronic exercise. The search for possible exercise/contraction-stimulated signaling proteins involved in glucose transport, muscle fiber type, and mitochondrial biogenesis is ongoing. Further research is needed because full elucidation of exercise-mediated signaling pathways would represent a significant step toward the development of new pharmacological targets for the treatment of metabolic diseases such as type 2 diabetes.

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Figures

Figure 1
Figure 1
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).
Figure 2
Figure 2
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.
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