Mitochondria mediate tumor necrosis factor-alpha/NF-kappaB signaling in skeletal muscle myotubes.
Tumor necrosis factor-alpha (TNF-alpha) is implicated in muscle atrophy and weakness associated with a variety of chronic diseases. Recently, we reported that TNF-alpha directly induces muscle protein degradation in differentiated skeletal muscle myotubes, where it rapidly activates nuclear factor kappaB (NF-kappaB). We also have found that protein loss induced by TNF-alpha is NF-kappaB dependent. In the present study, we analyzed the signaling pathway by which TNF-alpha activates NF-kappaB in myotubes differentiated from C2C12 and rat primary myoblasts. We found that activation of NF-kappaB by TNF-alpha was blocked by rotenone or amytal, inhibitors of complex I of the mitochondrial respiratory chain. On the other hand, antimycin A, an inhibitor of complex III, enhanced TNF-alpha activation of NK-kappaB. These results suggest a key role of mitochondria-derived reactive oxygen species (ROS) in mediating NF-kappaB activation in muscle. In addition, we found that TNF-alpha stimulated protein kinase C (PKC) activity. However, other signal transduction mediators including ceramide, Ca2+, phospholipase A2 (PLA2), and nitric oxide (NO) do not appear to be involved in the activation of NF-kappaB.
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Y P
YP
Li
C M
CM
Atkins
J D
JD
Sweatt
M B
MB
Reid
D000654:Amobarbital / Q000494:pharmacology; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002518:Ceramides / Q000737:chemistry / Q000494:pharmacology; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D008555:Melitten / Q000494:pharmacology; D008931:Mitochondria, Muscle / Q000378:metabolism*; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D009829:Oleic Acids; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism; D054467:Phospholipases A2; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D012430:Ruthenium Red / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D002518:Ceramides; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D016328:NF-kappa B; D009829:Oleic Acids; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D012402:Rotenone; C033595:N-oleoylethanolamine; D012430:Ruthenium Red; D008555:Melitten; D002110:Caffeine; D000968:Antimycin A; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D000654:Amobarbital; D009543:Nifedipine