Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

J Biol Chem. 2015 Dec 18;290(51):30269-79. doi: 10.1074/jbc.M115.685164. Epub 2015 Oct 29.

Abstract

NF-κB is best known for its pro-inflammatory and anti-apoptotic actions, but in skeletal muscle, NF-κB activation is important for atrophy upon denervation or cancer. Here, we show that also upon fasting, NF-κB becomes activated in muscle and is critical for the subsequent atrophy. Following food deprivation, the expression and acetylation of the p65 of NF-κB on lysine 310 increase markedly in muscles. NF-κB inhibition in mouse muscles by overexpression of the IκBα superrepressor (IκBα-SR) or of p65 mutated at Lys-310 prevented atrophy. Knockdown of GCN5 with shRNA or a dominant-negative GCN5 or overexpression of SIRT1 decreased p65K310 acetylation and muscle wasting upon starvation. In addition to reducing atrogene expression, surprisingly inhibiting NF-κB with IκBα-SR or by GCN5 knockdown in these muscles also enhanced AKT and mechanistic target of rapamycin (mTOR) activities, which also contributed to the reduction in atrophy. These new roles of NF-κB and GCN5 in regulating muscle proteolysis and AKT/mTOR signaling suggest novel approaches to combat muscle wasting.

Keywords: GCN5; NF-κB (NF-KB); acetylation; acetyltransferase; fasting; mTOR complex (mTORC); muscle atrophy; protein degradation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylation
  • Animals
  • Fasting / metabolism*
  • Male
  • Mice
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / genetics
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / pathology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / genetics
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism*

Substances

  • Rela protein, mouse
  • Transcription Factor RelA
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Sirt1 protein, mouse
  • Sirtuin 1