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

Donghoon Lee,Alfred L Goldberg

doi:10.1074/jbc.m115.685164

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.

Highlights

Muscle wasting and cachexia occur in various physiological and pathophysiological conditions, including fasting, denervation, inactivity, acidosis, sepsis, certain cancers, and in aged populations [1]
To determine whether NF-␬B may trigger muscle wasting during starvation, we tested if NF-␬B is activated in skeletal muscle upon food deprivation
Bicistronic DNA constructs encoding I␬B␣ superrepressor (I␬B␣-SR) and GFP were electroporated into Tibialis anterior (TA) muscles, and mice were deprived of food for 2 days and cross-sectional areas were measured

Summary

Introduction

Muscle wasting and cachexia occur in various physiological and pathophysiological conditions, including fasting, denervation, inactivity, acidosis, sepsis, certain cancers, and in aged populations [1]. Inhibition of NF-␬B by I␬B␣-SR Reduces Atrophy and Maintains AKT Activity—To determine whether the activation of NF-␬B is required for the loss of muscle mass upon starvation, we electroporated into the TA of fed mice bicistronic constructs encoding GFP to mark the electroporated fibers and a

Results

Conclusion