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TNF‐α‐induced loss of IKK‐α in skeletal muscle: implications for skeletal muscle oxidative phenotype
Author(s) -
Remels Alexander,
Langen Ramon,
Schols Annemie,
Gosker Harry
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.1144.2
Subject(s) - skeletal muscle , myogenesis , iκb kinase , myosin , endocrinology , myocyte , inflammation , medicine , c2c12 , biology , oxidative phosphorylation , chemistry , nf κb , microbiology and biotechnology , biochemistry
Molecular mechanisms underlying lower limb muscle dysfunction in chronic inflammatory disorders, e.g. chronic obstructive pulmonary disease (COPD), are unclear. Here we describe that IKK‐α, a key kinase in the alternative NF‐κB pathway, is a novel regulator of skeletal muscle oxidative phenotype (OXPHEN), which is targeted by inflammation. In C2C12 myotubes, IKK‐α knock‐down decreased myosin heavy chain (MyHC) slow protein and MyHC I and IIA (oxidative) mRNA levels while MyHC IIB (glycolytic) mRNA levels increased. Conversely, IKK‐α overexpression increased MyHC slow protein. Importantly, IKK‐α knock‐down decreased PGC‐1α and PGC‐1β mRNA levels, two key regulators of muscle OXPHEN. We previously demonstrated that TNF‐α potently impairs skeletal muscle OXPHEN (Remels et. al. FASEB J 2010). Interestingly, TNF‐α reduced IKK‐α protein, mRNA and promoter activity and diminished phosphorylation of the down‐stream target of IKK‐α in the alternative NF‐κB pathway (P100) in a classical NF‐κB dependent manner. IKK‐α protein levels in skeletal muscle tissue of COPD patients (n=34) were lower (−50%) compared to healthy controls (n=10). This data shows that IKK‐α controls skeletal muscle OXPHEN and suggests that TNF‐α‐induced loss of IKK‐α protein may contribute to loss of muscle OXPHEN in COPD. This study was supported by the Netherlands Asthma Foundation (3.2.09.068) and ENIGMA grant QLK6‐CT‐2002‐02285.