Abstract
The ubiquitin-proteasome system (UPS)-dependent proteolysis plays a major role in the muscle catabolic action of glucocorticoids (GCs). Atrogin-1 and muscle-specific RING finger protein 1 (MuRF1), two E3 ubiquitin ligases, are uniquely expressed in muscle. It has been previously demonstrated that GC treatment induced MuRF1 and atrogin-1 overexpression. However, it is yet unclear whether the higher pharmacological dose of GCs induced muscle protein catabolism through MuRF1 and atrogin-1. In the present study, the role of atrogin-1 and MuRF1 in C2C12 cells protein metabolism during excessive dexamethasone (DEX) was studied. The involvement of Akt/forkhead box O1 (FoXO1) signaling pathway and the cross-talk between anabolic regulator mammalian target of rapamycin (mTOR) and catabolic regulator FoXO1 were investigated. High concentration of DEX increased MuRF1 protein level in a time-dependent fashion (P<0.05), while had no detectable effect on atrogin-1 protein (P>0.05). FoXO1/3a (Thr24/32) phosphorylation was enhanced (P<0.05), mTOR phosphorylation was suppressed (P<0.05), while Akt protein expression was not affected (P>0.05) by DEX. RU486 treatment inhibited the DEX-induced increase of FoXO1/3a phosphorylation (P<0.05) and MuRF1 protein; LY294002 (LY) did not restore the stimulative effect of DEX on the FoXO1/3a phosphorylation (P>0.05), but inhibited the activation of MuRF1 protein induced by DEX (P<0.05); rapamycin (RAPA) inhibited the stimulative effect of DEX on the FoXO1/3a phosphorylation and MuRF1 protein (P<0.05).
Highlights
Skeletal muscle is an essential component of the body
We investigated whether excessive GCs enhanced proteolysis through the muscle-specific RING finger protein 1 (MuRF1) and atrogin-1, and the involvement of also known as Protein Kinase B (Akt)/forkhead box O1 (FoXO1) signaling pathway was evaluated
As a crucial protein synthesis regulator, mammalian target of rapamycin (mTOR) phosphorylation was suppressed by DEX (P
Summary
Skeletal muscle is an essential component of the body. The maintenance of skeletal muscle mass is of paramount importance for systemic energy homeostasis [1]. The muscle mass usually results from a dynamic balance between protein synthesis and catabolism [2]. When the body is suffering from severe stress, excessive glucocorticoids (GCs) in circulation cause muscular loss by impeding protein synthesis and enhancing protein breakdown [3,4,5]. GCs, as the final effectors of the hypothalamic–pituitary–adrenal axis, participate in the maintenance of whole-body homeostasis. Many pathological conditions, including muscle atrophy, result from an increase in circulating GC levels [6]
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