Mechanisms of Muscle Atrophy Induced by Glucocorticoids

Abstract

Background: Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoid (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy results from decreased protein synthesis and increased protein degradation. The inhibitory effect of GCs on protein synthesis is thought to result mainly from the inhibition of the p70 ribosomal S6 protein kinase. The stimulatory effect of GCs on muscle proteolysis results from the activation of two major cellular proteolytic systems: ubiquitin proteasome and lysosomal systems. The decrease in muscle production of insulin-like growth factor I (IGF-I), a muscle anabolic growth factor, could contribute to GC-induced muscle atrophy. By activating the phosphatidylinositol-3-kinase/Akt pathway, IGF-I overrides GC action to stunt muscle atrophy. Evidence also indicates that increased production of myostatin, a catabolic growth factor, could play a critical role in GC-induced muscle atrophy. Conclusions: Recent progress in understanding the role of growth factors in GC-induced muscle atrophy allows investigation into new therapies to minimize this myopathy.

Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy

“…Chronic steroid treatment has been associated with muscle atrophy (28). To understand how differential GC dosing altered muscle repair, we compared weekly steroid administration versus daily administration in WT mice after acute injury.…”

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

“…Mechanisms by which corticosteroids may impact muscle function are related to the ability of these agents to compromise the production of contractile proteins and down-regulate the IGF-1 pathway. Corticosteroids may also enhance proteolysis by increasing myostatin levels (385).…”

Muscle-specific MicroRNA1 (miR1) Targets Heat Shock Protein 70 (HSP70) during Dexamethasone-mediated Atrophy*

“…However, high doses and sustained usage of glucocorticoids result in muscle atrophy (2). The molecular mechanisms of glucocorticoid-induced muscle atrophy have been well studied and two muscle-specific E3 ubiquitin ligases, namely muscle ring finger protein 1 (MuRF1) 3 and Atrogin-1/MAFbx (muscle atrophy F-box) have been found to play a key role in glucocorticoid-induced atrophy (3)(4)(5)(6)(7)(8). MuRF1 and Atrogin-1 have been shown to ubiquitinate sarcomeric proteins, such as myosin heavy chain, which are then targeted for degradation through the ubiquitin proteosome pathway (9,10).…”

“…Mechanistically, dephosphorylation and thus activation of FOXO1 and FOXO3 results in their translocation into the nucleus where they transcriptionally activate MuRF1 and Atrogin-1 to induce atrophy. Activation of the insulin-like growth factor 1/PI3K/AKT pathway rescues dexamethasone (Dex)-mediated atrophy through phosphorylating and inactivating FOXO1/FOXO3 (5,7,12,13) implicating inhibition of this pathway as one of the main mechanisms behind Dex-induced atrophy.…”