Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy.
Although cytokine-induced nuclear factor kappaB (NF-kappaB) pathways are involved in muscle wasting subsequent to disease, their potential role in disuse muscle atrophy has not been characterized. Seven days of hind limb unloading led to a 10-fold activation of an NF-kappaB-dependent reporter in rat soleus muscle but not the atrophy-resistant extensor digitorum longus muscle. Nuclear levels of p50 were markedly up-regulated, c-Rel was moderately up-regulated, Rel B was down-regulated, and p52 and p65 were unchanged in unloaded solei. The nuclear IkappaB protein Bcl-3 was increased. There was increased binding to an NF-kappaB consensus oligonucleotide, and this complex bound antibodies to p50, c-Rel, and Bcl-3 but not other NF-kappaB family members. Tumor necrosis factor alpha (TNF-alpha) and TNF receptor-associated factor 2 protein were moderately down-regulated. There was no difference in p38, c-Jun NH(2)-terminal kinase or Akt activity, nor were activator protein 1 or nuclear factor of activated T cell-dependent reporters activated. Thus, whereas several NF-kappaB family members are up-regulated, the prototypical markers of cytokine-induced activation of NF-kappaB seen with disease-related wasting are not evident during disuse atrophy. Levels of an anti-apoptotic NF-kappaB target, Bcl-2, were increased fourfold whereas proapoptotic proteins Bax and Bak decreased. The evidence presented here suggests that disuse muscle atrophy is associated with activation of an alternative NF-kappaB pathway that involves the activation of p50 but not p65.
Hunter
R Bridge
RB
Boston University, Department of Health Sciences, Boston, Massachusetts 02215, USA.
Stevenson
EricJ
E
Koncarevic
Alan
A
Mitchell-Felton
Heather
H
Essig
David A
DA
Kandarian
Susan C
SC
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D002467:Cell Nucleus / Q000378:metabolism; D016384:Consensus Sequence; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D017930:Genes, Reporter; D019417:Hindlimb Suspension / Q000009:adverse effects; D051550:I-kappa B Kinase; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000081242:B-Cell Lymphoma 3 Protein; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase