Abstract:

ABSTRACT  Objective: The endogenous glucocorticoids (GC) is required for activation of muscle protein degradation in chronic kidney disease (CKD) related protein energy wasting. We studied the muscle wasting in a muscle specific glucocorticoids receptor knockout mouse (MGRKO) with CKD model. We hypothesis the MGRKO could suppress muscle atrophy. Methodology: MGRKO and lox/lox mice CKD model was made by 5/6 nephroctomy, and the sham was regarded as control (CTL). The serum corticosteroid hormone was measured by ELISA. The bodyweight and Tibia Anterior (TA) muscle weight were measured. The TA muscle size of was observed under microscope and calculated with software. The expression of Atrogin-1（Muscle Atrophy Fbox-1）and MuRF-1 (Muscle RING finger 1) was measured by Q-PCR and western blot. We also analyzed the signaling pathway of Akt/FoxO1. Results: The levels of serum BUN and corticosteroids were increased dramatically in lox/lox-CKD and MGRKO-CKD, but no differences between two groups. The bodyweight and TA muscle weight in the lox/lox-CKD was lower than that in the lox/lox- CTL L; but no difference between the MGKO-CTL and MGKO-CKD. The cross-sectional area of muscle fibers in the MGRKO-CKD was smaller, and the shrinkages of fibers sizes caused leftward shift in fiber size distribution was obvious in lox/lox-CKD, but only mild change in MGRKO+CKD mice’s muscle. The level of Atrogin-1 and MuRF-1 was increased dramatically, and the Akt/FoxO1 signaling pathway was abnormal which showed the level of phosphorylated Akt/FoxO1 repressive simultaneously in lox/lox-CKD (p<0.001). Whereas, the Atrogin-1 mRNA showed a mild higher (p<0.05), the MuRF-1 mRNA showed no difference, and the Akt/FoxO1 signaling abnormal was unconspicuous in the MGKO-CKD, which showed suppresses insulin/IGF-1 stimulation of Akt/FoxO1 activities. The MGRKO could resist to this abnormal, hence, ameliorate CKD induced muscle wasting. Conclusion: Endogenous Glucocorticoids (GC) may play an important role in CKD induced muscle wasting, muscle specific GC receptor knockout( MGRKO) can be resistant to muscle atrophy and loss of bodyweight induced by CKD. The mechanism might be MGRKO arrest the GC suppressing insulin/IGF-1 stimulation of Akt/FoxO1 activities, then, stop the active of Atrogin-1 and MuFR-1.

Key words: protein-energy wasting , chronic kidney disease  , glucocorticoids , gene knockout  , atrogin-1