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Regulation of skeletal muscle oxidative phenotype by classical NF‐κB signalling
Author(s) -
Remels Alexander,
Gosker Harry,
Schols Annemie,
Langen Ramon
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1144.1
Subject(s) - tfam , myogenesis , skeletal muscle , transcription factor , oxidative phosphorylation , inflammation , c2c12 , biology , iκb kinase , myocyte , tumor necrosis factor alpha , myosin , nf κb , microbiology and biotechnology , chemistry , mitochondrion , endocrinology , mitochondrial biogenesis , signal transduction , biochemistry , immunology , gene
Molecular mechanisms underlying loss of muscle oxidative phenotype (OXPHEN: intrinsic features determining fatigue resistance and capacity for substrate oxidation) in diseases associated with chronic systemic inflammation are unclear. In C2C12 myotubes, TNF‐α reduced protein and mRNA levels of myosin heavy chain (MyHC) slow and oxidative phosphorylation (OXPHOS) complex (I‐III) subunits. These effects of TNF‐α were blocked when classical NF‐κB signalling was genetically abrogated (C2C12‐IκBα‐SR). Accordingly, TNF‐α‐induced reductions in mRNA levels of the key OXPHEN regulators PGC‐ 1α and mitochondrial transcription factor A (Tfam) were attenuated in C2C12‐IκBα‐SR myotubes. Also, TNF‐α reduced mitochondrial fission (MTP18) and fusion (mfn‐2) mRNA expression in a classical NF‐κB‐dependent manner. In analogy, IL‐ 1β or over‐expression of P65/RelA or a constitutive active form of IKK‐β (key constituents of classical NF‐κB signalling) significantly decreased Tfam promoter trans‐activation as well as nuclear respiratory factor 1 (NRF‐1) transcriptional activity. This data shows that classical NF‐κB activation is both sufficient and required for TNF‐α‐induced impairment of skeletal muscle OXPHEN, which is relevant for several pathological conditions characterized by systemic inflammation and muscle dysfunction. This study was supported by the Netherlands Asthma Foundation ( 3.2.09.068 ).