Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes.
Mechanical stretch can activate muscle and myotube protein synthesis through mammalian target of rapamycin complex 1 (mTORC1) signaling. While it has been established that tumor-derived cachectic factors can induce myotube wasting, the effect of this catabolic environment on myotube mechanical signaling has not been determined. We investigated whether media containing cachectic factors derived from Lewis lung carcinoma (LLC) can regulate the stretch induction of myotube protein synthesis. C2C12 myotubes preincubated in control or LLC-derived media were chronically stretched. Protein synthesis regulation by anabolic and catabolic signaling was then examined. In the control condition, stretch increased mTORC1 activity and protein synthesis. The LLC treatment decreased basal mTORC1 activity and protein synthesis and attenuated the stretch induction of protein synthesis. LLC media increased STAT3 and AMP-activated protein kinase phosphorylation in myotubes, independent of stretch. Both stretch and LLC independently increased ERK1/2, p38, and NF-κB phosphorylation. In LLC-treated myotubes, the inhibition of ERK1/2 and p38 rescued the stretch induction of protein synthesis. Interestingly, either leukemia inhibitory factor or glycoprotein 130 antibody administration caused further inhibition of mTORC1 signaling and protein synthesis in stretched myotubes. AMP-activated protein kinase inhibition increased basal mTORC1 signaling activity and protein synthesis in LLC-treated myotubes, but did not restore the stretch induction of protein synthesis. These results demonstrate that LLC-derived cachectic factors can dissociate stretch-induced signaling from protein synthesis through ERK1/2 and p38 signaling, and that glycoprotein 130 signaling is associated with the basal stretch response in myotubes.
Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina; and.
Song
S
Gao
Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina; and Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina carsonj@mailbox.sc.edu.
James A
JA
Carson
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000378:metabolism; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009124:Muscle Proteins / Q000096:biosynthesis*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects; D010766:Phosphorylation; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D017077:Culture Media, Conditioned; C494200:Il6st protein, mouse; D018836:Inflammation Mediators; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases
AMPK; MAP kinase; cachexia; gp130; mTORC1