title: Tumor necrosis factor alpha (TNF-α) inactivates the PI3-kinase/PKB pathway and induces atrophy and apoptosis in L6 myotubes.
abstract: Muscle atrophy poses a serious concern to patients inflicted with inflammatory diseases. An increasing body of evidence implies that TNF-α plays a critical role in muscle atrophy in a number of these clinical settings. The mechanisms mediating its effects are not completely understood and conflicting data regarding its anabolic and catabolic actions exists. To examine the functional significance and detailed morphological characteristics of TNF-α-induced muscle proteolysis, differentiated L6 myotubes were subjected to increasing concentrations of recombinant TNF-α for 24 and 48 h. Data analysis of cell death showed that TNF-α induced a combination of apoptosis and necrosis in high concentrations. TNF-R1, rather than TNF-R2, was significantly upregulated. In addition, the transcription factors, NF-κB and FKHR were rapidly activated thus leading to increased expression of ubiquitin ligases, MuRF-1 and MAFbx. Muscle fiber diameter decreased with increasing TNF-α concentrations and was associated with attenuation of the PI3-K/Akt pathway as well as significant reductions in differentiation markers. Furthermore, treatment of L6 myotubes with exogenous TNF-α strongly potentiates its proteolytic effects through certain MAPKs that are activated. These observations suggest that TNF-α induces muscle proteolysis in a dose-dependent manner via various signal transduction pathways.
authors.affiliation: Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa. 14088568@sun.ac.za
authors.forename: Balindiwe J N
authors.initials: BJ
authors.lastname: Sishi
authors.forename: Anna-Mart
authors.initials: AM
authors.lastname: Engelbrecht
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007150:Immunohistochemistry; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D051057:Proto-Oncogene Proteins c-akt