TRAF6 inhibition rescues dexamethasone-induced muscle atrophy.

Hualin Sun,Fei Ding,Yanfei Chen,Jiaying Qiu,Qing Zhao,Yanpei Gong

doi:10.3390/ijms150611126

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6), a unique E3 ubiquitin ligase and adaptor protein, is involved in activation of various signaling cascades. Recent studies identify TRAF6 as one of the novel regulators of skeletal muscle atrophy. The role of TRAF6 in glucocorticoid-induced muscle atrophy, however, remains to be elucidated. In this study, we show that TRAF6 and its downstream signaling molecules, muscle atrophy F-box (MAFBx) and muscle ring finger 1 (MuRF1), were all upregulated in dexamethasone-induced atrophy of mouse C2C12 myotubes or mouse tibialis anterior (TA) muscle. To further investigate the role of TRAF6 in dexamethasone-induced muscle atrophy, TRAF6-siRNA was used to transfect cultured C2C12 myotubes or was injected into the TA muscle of mice respectively, and we note that TRAF6 knockdown attenuated dexamethasone-induced muscle atrophy in vitro and in vivo, and concomitantly decreased the expression of MuRF1 and MAFBx. Our findings suggest that a decreased expression of TRAF6 could rescue dexamethasone-induced skeletal muscle atrophy through, at least in part, regulation of the expression of MAFBx and MuRF1.

Highlights

Skeletal muscle atrophy, resulting from increased myofibrillar protein breakdown, is a complex biochemical process occurring under various pathophysiological conditions, such as aging, disuse, starvation, severe injury, sepsis, cancer and other cachectic diseases [1,2,3,4]
The expression of Tumor necrosis factor receptor-associated factor 6 (TRAF6), muscle atrophy F-box (MAFBx), and muscle ring finger 1 (MuRF1) at the mRNA and protein levels in tibialis anterior (TA) muscles of mice treated with 10 mg/kg Dex was significantly increased compared to that treated with vehicle, respectively, as determined by Quantitative RT-PCR (qPCR) and Western blot analysis, respectively (Figure 2)
Western blot analysis indicated that the protein expression of TRAF6, MAFBx, or MuRF1 was higher in Dex-stimulated C2C12

Summary

Introduction

Skeletal muscle atrophy, resulting from increased myofibrillar protein breakdown, is a complex biochemical process occurring under various pathophysiological conditions, such as aging, disuse, starvation, severe injury, sepsis, cancer and other cachectic diseases [1,2,3,4]. A number of explanations have been proposed [5,7,10,11,12], the precise molecular mechanisms by which glucocorticoids induce muscle atrophy are not well understood. Considerable attention has been focused on the understanding of molecular mechanisms responsible for dexamethasone-induced muscle atrophy and the development of novel therapeutic strategies. Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) is a member of TRAF family, and it functions as a crucial signaling molecule to regulate a diverse array of physiological processes, including innate immunity, adaptive immunity, bone metabolism, and the development of mammary glands, lymph nodes, skin and the central nervous system [13]. Among TRAF family members, TRAF6 has unique properties, which enable it to mediate tumor necrosis factor receptor (TNFR) family signaling, and to affect signaling downstream of an unrelated family of receptors, the interleukin-1

Results

Discussion

Conclusion