TNF- α and IFN-s-dependent muscle decay is linked to NF-κB- and STAT-1α-stimulated Atrogin1 and MuRF1 genes in C2C12 myotubes.
TNF-α was shown to stimulate mitogenicity in C2C12 myoblasts. Selected cytokines TNF-α, IFNα, or IFNγ reduced the expression of myosin heavy chain (MyHC IIa) when given together. Molecular mechanisms of cytokine activities were controlled by NF-κB and JAK/STAT signaling pathways, as metabolic inhibitors, curcumin and AG490, inhibited some of TNF-α and IFNα/IFNγ effects. Insulin was hardly antagonistic to TNF-α - and IFNα/IFNγ-dependent decrease in MyHC IIa protein expression. Cytokines used individually or together also repressed myogenesis of C2C12 cells. Moreover, TNF-α - and IFNα/IFNγ-dependent effects on C2C12 myotubes were associated with increased activity of Atrogin1 and MuRF1 genes, which code ubiquitin ligases. MyHC IIa gene activity was unaltered by cytokines. Inhibition of NF-κB or JAK/STAT with specific metabolic inhibitors decreased activity of Atrogin1 and MuRF1 but not MyHC IIa gene. Overall, these results suggest cooperation between cytokines in the reduction of MyHC IIa protein expression level via NF-κB/JAK/STAT signaling pathways and activation of Atrogin1 and MuRF1 genes as their molecular targets. Insulin cotreatment or pretreatment does not protect against muscle decay induced by examined proinflammatory cytokines.
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
Barbara
B
Pijet
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
Maja
M
Pijet
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
Anna
A
Litwiniuk
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland.
Małgorzata
M
Gajewska
Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
Beata
B
Pająk
Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland ; Electron Microscopy Platform, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
Arkadiusz
A
Orzechowski
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D050832:Interferon-Stimulated Gene Factor 3 / Q000502:physiology*; D007372:Interferons / Q000494:pharmacology*; D053612:Janus Kinases / Q000502:physiology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D053199:TNF Receptor-Associated Death Domain Protein / Q000032:analysis; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D007328:Insulin; D050832:Interferon-Stimulated Gene Factor 3; D009124:Muscle Proteins; D016328:NF-kappa B; D053199:TNF Receptor-Associated Death Domain Protein; C481226:Tradd protein, mouse; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; C079868:gamma interferon activation factor; D007372:Interferons; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053612:Janus Kinases; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains; D003474:Curcumin