%0 Journal Article
%T TNF- ¦Á and IFN-s-Dependent Muscle Decay Is Linked to NF- B- and STAT-1 ¦Á -Stimulated Atrogin1 and MuRF1 Genes in C2C12 Myotubes
%A Barbara Pijet
%A Maja Pijet
%A Anna Litwiniuk
%A Ma£¿gorzata Gajewska
%A Beata Paj£¿k
%A Arkadiusz Orzechowski
%J Mediators of Inflammation
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/171437
%X TNF-¦Á was shown to stimulate mitogenicity in C2C12 myoblasts. Selected cytokines TNF-¦Á, IFN¦Á, or IFN¦Ã reduced the expression of myosin heavy chain (MyHC IIa) when given together. Molecular mechanisms of cytokine activities were controlled by NF-¦ÊB and JAK/STAT signaling pathways, as metabolic inhibitors, curcumin and AG490, inhibited some of TNF-¦Á and IFN¦Á/IFN¦Ã effects. Insulin was hardly antagonistic to TNF-¦Á- and IFN¦Á/IFN¦Ã-dependent decrease in MyHC IIa protein expression. Cytokines used individually or together also repressed myogenesis of C2C12 cells. Moreover, TNF-¦Á- and IFN¦Á/IFN¦Ã-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-¦ÊB 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-¦ÊB/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. 1. Introduction Cachexia, an unintentional loss of lean body weight despite adequate nutrition, is a fatal complication of many diseases (cancer, congestive heart failure, diabetes, kidney failure, chronic obstructive pulmonary disease, rheumatoid arthritis, and HIV/AIDS), while the primary causal molecular mechanisms still remain unknown [1, 2]. Actually, it seems obvious that all these complications have something in common despite distinct etiology. Among several hypotheses, the insufficient anabolic action of insulin in response to rise in some cytokines during systemic inflammation attracted our attention. The loss of muscle tissue observed in elevated levels of proinflammatory cytokines seems to be linked to accelerated proteolysis rather than impaired protein synthesis [3]. Some authors [4] observed synergism between TNF-¦Á and IFN-¦Ã effects through NF-¦ÊB activation. Moreover, Guttridge et al. [5] demonstrated that inhibition of myogenesis is NF-¦ÊB dependent, as cytokine activation is responsible for the reduction of MyoD protein that controls muscle development [6]. Furthermore, as reported by Wheeler et al. [7], MyoD binding to myosin heavy chain IIb promoter region is necessary for myosin expression in fast twitch muscles. Interestingly, IGF-1 could not stop the effect of proinflammatory cytokines in myotube
%U http://www.hindawi.com/journals/mi/2013/171437/