title: Regulation of a Notch3-Hes1 pathway and protective effect by a tocopherol-omega alkanol chain derivative in muscle atrophy.
abstract: Muscular atrophy, a physiopathologic process associated with severe human diseases such as amyotrophic lateral sclerosis (ALS) or cancer, has been linked to reactive oxygen species (ROS) production. The Notch pathway plays a role in muscle development and in muscle regeneration upon physical injury. In this study, we explored the possibility that the Notch pathway participates in the ROS-related muscular atrophy occurring in cancer-associated cachexia and ALS. We also tested whether hybrid compounds of tocopherol, harboring antioxidant activity, and the omega-alkanol chain, presenting cytoprotective activity, might reduce muscle atrophy and impact the Notch pathway. We identified one tocopherol-omega alkanol chain derivative, AGT251, protecting myoblastic cells against known cytotoxic agents. We showed that this compound presenting antioxidant activity counteracts the induction of the Notch pathway by cytotoxic stress, leading to a decrease of Notch1 and Notch3 expression. At the functional level, these regulations correlated with a repression of the Notch target gene Hes1 and the atrophy/remodeling gene MuRF1. Importantly, we also observed an induction of Notch3 and Hes1 expression in two murine models of muscle atrophy: a doxorubicin-induced cachexia model and an ALS murine model expressing mutated superoxide dismutase 1. In both models, the induction of Notch3 and Hes1 were partially opposed by AGT251, which correlated with ameliorations in body and muscle weight, reduction of muscular atrophy markers, and improved survival. Altogether, we identified a compound of the tocopherol family that protects against muscle atrophy in various models, possibly through the regulation of the Notch pathway.
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.).
authors.forename: Yannick
authors.initials: Y
authors.lastname: von Grabowiecki
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Licona
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.).
authors.forename: Lavinia
authors.initials: L
authors.lastname: Palamiuc
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.).
authors.forename: Paula
authors.initials: P
authors.lastname: Abreu
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.).
authors.forename: Vania
authors.initials: V
authors.lastname: Vidimar
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.).
authors.forename: Djalil
authors.initials: D
authors.lastname: Coowar
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.).
authors.forename: Georg
authors.initials: G
authors.lastname: Mellitzer
authors.affiliation: INSERM U1113, Molecular Mechanisms of Stress Response and Pathologies, Strasbourg, France (Y.v.G., C.L., P.A., V.V., G.M., C.G.); Faculté de Médecine de Strasbourg, Strasbourg University, Strasbourg, France (Y.v.G., C.L., L.P., P.A., V.V., G.M., C.G.); and AxoGlia Therapeutics, Fentange, Luxembourg (D.C.) Gaiddon@unistra.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Gaiddon
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002100:Cachexia / Q000139:chemically induced / Q000517:prevention & control; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000009:adverse effects; D005419:Flavonoids / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D024505:Tocopherols / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000072056:Transcription Factor HES-1
chemical_list: D000438:Alcohols; D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D004317:Doxorubicin; D005419:Flavonoids; D018398:Homeodomain Proteins; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D024505:Tocopherols; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C499373:Notch3 protein, mouse