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Author Notes:

Zhaoyong Hu, Baylor College of Medicine, Nephrology Division M/S: BCM 395, One Baylor Plaza, ABBR R702, Houston, Texas 77030, USA, zhaoyonh@bcm.edu.

We thank Dr. William E. Mitch for helpful comments and encouragement.

The authors declare there are not conflicts of interest in generating or reporting our results

Subjects:

Research Funding:

The work was supported by NIH Grants R37 DK37175. Jing Xu was supported by Shanghai Health Bureau of dcientific research grant (07JG137) and Shanghai Municipal Education Commission grant (12zz075).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Urology & Nephrology
  • chronic kidney disease (CKD)
  • FoxO1
  • microRNA
  • miR-486
  • muscle wasting
  • SKELETAL-MUSCLE
  • MESSENGER-RNA
  • PROTEIN-DEGRADATION
  • PROTEASOME ACTIVITY
  • UBIQUITIN LIGASES
  • ATROPHY
  • EXPRESSION
  • PATHWAY
  • DIFFERENTIATION
  • METABOLISM

Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486

Journal Title:

Kidney International

Volume:

Volume 82, Number 4

Publisher:

, Pages 401-411

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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.

Copyright information:

© 2012 International Society of Nephrology.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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