Glucocorticoid-induced skeletal muscle atrophy

Abstract

Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Keywords: 11β-HSD1; 11β-hydroxysteroid dehydrogenase type 1; 4E-BP1; BCAA; BCAT; C/EBP; CCAAT/enhancer binding protein; EDL; FOXO; GC; GHSR1; GR; GRE; GSK3β; Gadd45; Glucocorticoids; HAT; HDAC; HMB; IGF-I; IRS-1; Insulin-like Growth Factor-I; Insulin-like Growth Factors; KLF-15; Kruppel-like factor 15; LC3; MYHC; Mstn; MuRF-1; Myostatin; NFκB; PDK4; PI3K; Protein synthesis; Protein turnover; REDD1; S6K1; SARM; Skeletal muscle; UPS; branched-chain amino acid; branched-chain amino acid aminotransferase; eIF2B; eIF3F; eIF4E; eukaryotic initiation factor 2B; eukaryotic translation initiation factor 3 subunit F; eukaryotic translation initiation factor 4E; eukaryotic translation initiation factor 4E-binding protein 1; extensor digitorum longus; forkhead box O; glucocorticoid receptor; glucocorticoid-responsive element; glucocorticoids; glycogen synthase kinase 3β; growth arrest and DNA damage; growth hormone secretagogue receptor 1; histone acetyltransferases; histone deacetylases; insulin receptor substrate 1; mTOR; mammalian target of rapamycin; miR1; microRNA 1; microtubule-associated protein light chain 3; muscle RING-finger protein-1; myosin heavy chain; nuclear factor-kappa B; phosphatidylinositol 3′ kinase; pyruvate dehydrogenase kinase 4; regulated in development and DNA damage responses 1; ribosomal protein kinase 1; selective androgen receptor modulator; siRNA; small interfering RNA; ubiquitin proteasome system; β-hydroxy-β-methylbutyrate.