Muscle wasting in fasting requires activation of NF-{kappa}B and inhibition of AKT/mTOR by the protein acetylase, GCN5 [Molecular Bases of Disease]

October 29th, 2015 by Lee, D., Goldberg, A. L.

NF-κB is best known for its proinflammatory 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 NF-kκB's p65 subunit 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 K310 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 mTORactivities, 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.
  • Posted in Journal of Biological Chemistry, Publications
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