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

Kidney Int. 2012 Aug;82(4):401-11. doi: 10.1038/ki.2012.84.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Disease Models, Animal
  • Electroporation
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Glucocorticoids / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Fibers, Skeletal / pathology
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / etiology*
  • Muscular Atrophy / genetics
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology
  • Muscular Atrophy / prevention & control
  • Oligonucleotides / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Renal Insufficiency, Chronic / complications*
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism
  • Renal Insufficiency, Chronic / pathology
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Time Factors
  • Transfection
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Glucocorticoids
  • MIRN486 microRNA, mouse
  • MicroRNAs
  • Muscle Proteins
  • Oligonucleotides
  • Tripartite Motif Proteins
  • Dexamethasone
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Proteasome Endopeptidase Complex