PMID- 21256828 OWN - NLM STAT- MEDLINE DCOM- 20110406 LR - 20221207 IS - 1090-2104 (Electronic) IS - 0006-291X (Print) IS - 0006-291X (Linking) VI - 405 IP - 3 DP - 2011 Feb 18 TI - Inhibition of IkappaB kinase alpha (IKKalpha) or IKKbeta (IKKbeta) plus forkhead box O (Foxo) abolishes skeletal muscle atrophy. PG - 491-6 LID - 10.1016/j.bbrc.2011.01.059 [doi] AB - Two transcription factor families that are activated during multiple conditions of skeletal muscle wasting are nuclear factor kappaB (NF-kappaB) and forkhead box O (Foxo). There is clear evidence that both NF-kappaB and Foxo activation are sufficient to cause muscle fiber atrophy and they are individually required for at least half of the fiber atrophy during muscle disuse, but there is no work determining the combined effect of inhibiting these factors during a physiological condition of muscle atrophy. Here, we determined whether inhibition of Foxo activation plus inhibition of NF-kappaB activation, the latter by blocking the upstream inhibitor of kappaB kinases (IKKalpha and IKKbeta), would prevent muscle atrophy induced by 7 days of cast immobilization. Results were based on measurements of mean fiber cross-sectional area (CSA) from 72 muscles transfected with 5 different mutant expression plasmids or plasmid combinations. Immobilization caused a 47% decrease in fiber CSA in muscles injected with control plasmids. Fibers from immobilized muscles transfected with dominant negative (d.n.) IKKalpha-EGFP, d.n. IKKbeta-EGFP or d.n. Foxo-DsRed showed a 22%, 57%, and 76% inhibition of atrophy, respectively. Co-expression of d.n. IKKalpha-EGFP and d.n. Foxo-DsRed significantly inhibited 89% of the immobilization-induced fiber atrophy. Similarly, co-expression of d.n. IKKbeta-EGFP and d.n. Foxo-DsRed inhibited the immobilization-induced fiber atrophy by 95%. These findings demonstrate that the combined effects of inhibiting immobilization-induced NF-kappaB and Foxo transcriptional activity has an additive effect on preventing immobilization-induced atrophy, indicating that NF-kappaB and Foxo have a cumulative effect on atrophy signaling and/or atrophy gene expression. CI - Copyright (c) 2011 Elsevier Inc. All rights reserved. FAU - Reed, S A AU - Reed SA AD - Department of Physical Therapy, University of Florida, 101 S. Newell Drive, Gainesville, FL 32610, USA. FAU - Senf, S M AU - Senf SM FAU - Cornwell, E W AU - Cornwell EW FAU - Kandarian, S C AU - Kandarian SC FAU - Judge, A R AU - Judge AR LA - eng GR - R01AR41705/AR/NIAMS NIH HHS/United States GR - R03AR056418/AR/NIAMS NIH HHS/United States GR - P30 AG028740/AG/NIA NIH HHS/United States GR - R03 AR056418/AR/NIAMS NIH HHS/United States GR - R01 AR041705/AR/NIAMS NIH HHS/United States GR - R03 AR056418-02/AR/NIAMS NIH HHS/United States GR - T32-HD-043730/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110121 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - 0 (Forkhead Transcription Factors) RN - 0 (Nerve Tissue Proteins) RN - 0 (Foxo1 protein, rat) RN - EC 2.7.11.10 (I-kappa B Kinase) SB - IM MH - Animals MH - Forkhead Transcription Factors/*antagonists & inhibitors/genetics/metabolism MH - I-kappa B Kinase/*antagonists & inhibitors/genetics/metabolism MH - Male MH - Muscle, Skeletal/*metabolism/pathology MH - Muscular Atrophy/*genetics/pathology MH - Nerve Tissue Proteins/*antagonists & inhibitors/genetics/metabolism MH - Plasmids/genetics MH - Rats MH - Rats, Sprague-Dawley MH - Transcription, Genetic PMC - PMC3056397 MID - NIHMS267187 EDAT- 2011/01/25 06:00 MHDA- 2011/04/07 06:00 PMCR- 2012/02/18 CRDT- 2011/01/25 06:00 PHST- 2011/01/03 00:00 [received] PHST- 2011/01/17 00:00 [accepted] PHST- 2011/01/25 06:00 [entrez] PHST- 2011/01/25 06:00 [pubmed] PHST- 2011/04/07 06:00 [medline] PHST- 2012/02/18 00:00 [pmc-release] AID - S0006-291X(11)00089-1 [pii] AID - 10.1016/j.bbrc.2011.01.059 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2011 Feb 18;405(3):491-6. doi: 10.1016/j.bbrc.2011.01.059. Epub 2011 Jan 21.