title: Myostatin gene inactivation prevents skeletal muscle wasting in cancer.
abstract: Cachexia is a muscle-wasting syndrome that contributes significantly to morbidity and mortality of many patients with advanced cancers. However, little is understood about how the severe loss of skeletal muscle characterizing this condition occurs. In the current study, we tested the hypothesis that the muscle protein myostatin is involved in mediating the pathogenesis of cachexia-induced muscle wasting in tumor-bearing mice. Myostatin gene inactivation prevented the severe loss of skeletal muscle mass induced in mice engrafted with Lewis lung carcinoma (LLC) cells or in Apc(Min) (/+) mice, an established model of colorectal cancer and cachexia. Mechanistically, myostatin loss attenuated the activation of muscle fiber proteolytic pathways by inhibiting the expression of atrophy-related genes, MuRF1 and MAFbx/Atrogin-1, along with autophagy-related genes. Notably, myostatin loss also impeded the growth of LLC tumors, the number and the size of intestinal polyps in Apc(Min) (/+) mice, thus strongly increasing survival in both models. Gene expression analysis in the LLC model showed this phenotype to be associated with reduced expression of genes involved in tumor metabolism, activin signaling, and apoptosis. Taken together, our results reveal an essential role for myostatin in the pathogenesis of cancer cachexia and link this condition to tumor growth, with implications for furthering understanding of cancer as a systemic disease.
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France.
authors.forename: Yann S
authors.initials: YS
authors.lastname: Gallot
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France.
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Durieux
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France.
authors.forename: Josiane
authors.initials: J
authors.lastname: Castells
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France.
authors.forename: Marine M
authors.initials: MM
authors.lastname: Desgeorges
authors.affiliation: INRA UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vernus
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Plantureux
authors.affiliation: INRA UMR 1019, Unité de Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Rémond
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France.
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Jahnke
authors.affiliation: INSERM U1060, INRA USC1235, CarMeN Laboratory, Université de Lyon, Oullins, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.affiliation: INRA UMR 1019, Unité de Nutrition Humaine, Clermont-Ferrand, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Dardevet
authors.affiliation: INSERM U1060, INRA USC1235, CarMeN Laboratory, Université de Lyon, Oullins, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Nemoz
authors.affiliation: CNRS UMR 5239, Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Schaeffer
authors.affiliation: INRA UMR 866 Dynamique Musculaire et Métabolisme, Montpellier, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bonnieu
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France. damien.freyssenet@univ-st-etienne.fr.
authors.forename: Damien G
authors.initials: DG
authors.lastname: Freyssenet
mesh_terms: D000818:Animals; D002100:Cachexia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C525912:Mstn protein, mouse; D055435:Myostatin