title: Localized LoxL3-Dependent Fibronectin Oxidation Regulates Myofiber Stretch and Integrin-Mediated Adhesion.
abstract: For muscles to function, myofibers have to stretch and anchor at the myotendinous junction (MTJ), a region rich in extracellular matrix (ECM). Integrin signaling is required for MTJ formation, and mutations affecting the cascade lead to muscular dystrophies in mice and humans. Underlying mechanisms for integrin activation at the MTJ and ECM modifications regulating its signaling are unclear. We show that lysyl oxidase-like 3 (LoxL3) is a key regulator of integrin signaling that ensures localized control of the cascade. In LoxL3 mutants, myofibers anchor prematurely or overshoot to adjacent somites, and are loose and lack tension. We find that LoxL3 complexes with and directly oxidizes Fibronectin (FN), an ECM scaffold protein and integrin ligand enriched at the MTJ. We identify a mechanism whereby localized LoxL3 secretion from myofiber termini oxidizes FN, enabling enhanced integrin activation at the tips of myofibers and ensuring correct positioning and anchoring of myofibers along the MTJ.
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Kraft-Sheleg
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Zaffryar-Eilot
authors.affiliation: Department of Poultry and Aquaculture, Institute of Animal Sciences, Agricultural Research Organization, The Volcani Center, Bet Dagan 50250, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Genin
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Wesal
authors.initials: W
authors.lastname: Yaseen
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Soueid-Baumgarten
authors.affiliation: Cancer Research and Vascular Biology Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Kessler
authors.affiliation: Cancer Research and Vascular Biology Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Smolkin
authors.affiliation: Cancer Research and Vascular Biology Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Akiri
authors.affiliation: Cancer Research and Vascular Biology Center, The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.affiliation: Department of Poultry and Aquaculture, Institute of Animal Sciences, Agricultural Research Organization, The Volcani Center, Bet Dagan 50250, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Cinnamon
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel. Electronic address: phasson@tx.technion.ac.il.
authors.forename: Peleg
authors.initials: P
authors.lastname: Hasson
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism; D010084:Oxidation-Reduction; D019170:Somites / Q000378:metabolism; D013710:Tendons / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016023:Integrins; D000594:Amino Acid Oxidoreductases; C511777:LOXL3 protein, mouse