期刊
KIDNEY INTERNATIONAL
卷 82, 期 4, 页码 401-411出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2012.84
关键词
chronic kidney disease (CKD); FoxO1; microRNA; miR-486; muscle wasting
资金
- NIH [R37 DK37175]
- Shanghai Health Bureau of Scientific Research [07JG137]
- Shanghai Municipal Education Commission [12ZZ075]
Chronic kidney disease (CKD) accelerates muscle protein degradation by stimulating the ubiquitin proteasome system through activation of the E3 ligases, Atrogin-1/MAFbx and MuRF-1. Forkhead transcription factors (FoxOs) can control the expression of these E3 ligases, but the contribution of individual FoxOs to muscle wasting is unclear. To study this we created mice with a muscle-specific FoxO1 deletion. The absence of FoxO1 blocked 70% of the increase in E3 ligase induction by CKD as well as the proteolysis and loss of muscle mass. Thus, FoxO1 has a role in controlling ubiquitin proteasome system-related proteolysis. As microRNA (miR)-486 reportedly dampens FoxO1 expression and its activity, we transfected a miR-486 mimic into primary cultures of myotubes and found this blocked dexamethasone-stimulated protein degradation without influencing protein synthesis. It also decreased FoxO1 protein translation and increased FoxO1 phosphorylation by downregulation of PTEN phosphatase, a negative regulator of p-Akt. To test its efficacy in vivo, we electroporated miR-486 into muscles and found that the expression of the E3 ligases was suppressed and muscle mass increased despite CKD. Thus, FoxO1 is a dominant mediator of CKD-induced muscle wasting, and miR-486 coordinately decreases FoxO1 and PTEN to protect against this catabolic response. Kidney International (2012) 82, 401-411; doi:10.1038/ki.2012.84; published online 4 April 2012
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