1642-P: Deferoxamine Prevented Dexamethasone-Induced Muscle Atrophy through Inhibition of KLF15 and FOXO3a

Abstract

Aim/hypothesis: Muscle atrophy is caused by various factors such as aging, a lack of exercise, and diseases. During these events, the balance between protein synthesis and degradation is disrupted and finally muscle mass is decreased. This has been reported to occur via the ubiquitin-proteasome dependent pathway, autophagy, or apoptosis. In this study, we investigated the main mechanisms of dexamethasone-induced muscle atrophy and preventing mechanisms of deferoxamine on DEX-induced muscle atrophy. Method: To measure the effects of DFO on muscle atrophy, C2C12 myotubes were treated with dexamethasone, with or without DFO, then myotubes atrophy was measured by phalloidin staining, RT-PCR, and western blotting. Results: In differentiated C2C12 myotubes, DEX induced muscle atrophy in a time- and dose-dependent manner. DEX induced expressions of muscle-specific ligases, including muscle ring finger 1 and muscle atrophy F box, and activated the ubiquitin-proteasome system leading to muscle atrophy, not autophagy or apoptosis. Interestingly, DFO administration alleviated DEX-induced myotubes atrophy. DFO inhibited DEX-activated expressions of KLF15, not REDD or FOXO3a. DFO dramatically diminished FOXO3a translocation from cytosol to nucleus through the activation of AKT. Finally, expressions of muscle-specific ligases, such as MURF1 and Atrogin-1, were reduced by treatment of DFO, and ubiquitinated myoprotein was also reduced. In addition, mice treated with DEX for 12 days had a significant decrease in grip strength and TA muscle mass. However, treatment with DFO prevented DEX-induced reduction of muscle fiber size, loss of TA muscle, and grip strength. Conclusion: DEX activated muscle specific E3 ligase and induced-muscle atrophy through ubiquitin-proteasome system. DFO ameliorates muscle atrophy by inhibition of E3 ligase expression via KLF15 and FOXO3a in DEX-treated C2C12 myotubes and C57BL6J mice. Disclosure Y.Kim: None. H.Kim: None. D.Kim: None. T.Kim: None. S.An: None. K.Lee: None. N.Lee: None. S.Choi: None. Y.Kim: None. Y.Son: None. S.Choi: None. Y.Y.Kang: None. J.Jeon: None. S.Han: None.