title: Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5.
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.
authors.affiliation: From the Department of Cell Biology, Harvard Medical School, Boston, Masachusetts 02115.
authors.forename: Donghoon
authors.initials: D
authors.lastname: Lee
authors.affiliation: From the Department of Cell Biology, Harvard Medical School, Boston, Masachusetts 02115 alfred_goldberg@hms.harvard.edu.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Goldberg
mesh_terms: D000107:Acetylation; D000818:Animals; D005215:Fasting / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D056564:Sirtuin 1; D058570:TOR Serine-Threonine Kinases; D051996:Transcription Factor RelA; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C498144:Rela protein, mouse; C546843:mTOR protein, mouse; C470545:Sirt1 protein, mouse
keywords: GCN5; NF-κB (NF-KB); acetylation; acetyltransferase; fasting; mTOR complex (mTORC); muscle atrophy; protein degradation