title: Myostatin is a novel tumoral factor that induces cancer cachexia.
abstract: Humoral and tumoral factors collectively promote cancer-induced skeletal muscle wasting by increasing protein degradation. Although several humoral proteins, namely TNFα (tumour necrosis factor α) and IL (interleukin)-6, have been shown to induce skeletal muscle wasting, there is a lack of information regarding the tumoral factors that contribute to the atrophy of muscle during cancer cachexia. Therefore, in the present study, we have characterized the secretome of C26 colon cancer cells to identify the tumoral factors involved in cancer-induced skeletal muscle wasting. In the present study, we show that myostatin, a procachectic TGFβ (transforming growth factor β) superfamily member, is abundantly secreted by C26 cells. Consistent with myostatin signalling during cachexia, treating differentiated C2C12 myotubes with C26 CM (conditioned medium) resulted in myotubular atrophy due to the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1 (muscle RING-finger protein 1), and enhanced activity of the ubiquitin-proteasome pathway. Furthermore, the C26 CM also activated ActRIIB (activin receptor type II B)/Smad and NF-κB (nuclear factor κB) signalling, and reduced the activity of the IGF-I (insulin-like growth factor 1)/PI3K (phosphoinositide 3-kinase)/Akt pathway, three salient molecular features of myostatin action in skeletal muscles. Antagonists to myostatin prevented C26 CM-induced wasting in muscle cell cultures, further confirming that tumoral myostatin may be a key contributor in the pathogenesis of cancer cachexia. Finally, we show that treatment with C26 CM induced the autophagy-lysosome pathway and reduced the number of mitochondria in myotubes. These two previously unreported observations were recapitulated in skeletal muscles collected from C26 tumour-bearing mice.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Sudarsanareddy
authors.initials: S
authors.lastname: Lokireddy
authors.forename: Isuru Wijerupage
authors.initials: IW
authors.lastname: Wijesoma
authors.forename: Sabeera
authors.initials: S
authors.lastname: Bonala
authors.forename: Meng
authors.initials: M
authors.lastname: Wei
authors.forename: Siu Kwan
authors.initials: SK
authors.lastname: Sze
authors.forename: Craig
authors.initials: C
authors.lastname: McFarlane
authors.forename: Ravi
authors.initials: R
authors.lastname: Kambadur
authors.forename: Mridula
authors.initials: M
authors.lastname: Sharma
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism; D028341:Activins / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D002100:Cachexia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects; D055435:Myostatin / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017077:Culture Media, Conditioned; D055435:Myostatin; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C422405:activin A; D028341:Activins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B