title: Muscle composition is regulated by a Lox-TGFβ feedback loop.
abstract: Muscle is an integrated tissue composed of distinct cell types and extracellular matrix. While much emphasis has been placed on the factors required for the specification of the cells that comprise muscle, little is known about the crosstalk between them that enables the development of a patterned and functional tissue. We find in mice that deletion of lysyl oxidase (Lox), an extracellular enzyme regulating collagen maturation and organization, uncouples the balance between the amount of myofibers and that of muscle connective tissue (MCT). We show that Lox secreted from the myofibers attenuates TGFβ signaling, an inhibitor of myofiber differentiation and promoter of MCT development. We further demonstrate that a TGFβ-Lox feedback loop between the MCT and myofibers maintains the dynamic developmental homeostasis between muscle components while also regulating MCT organization. Our results allow a better understanding of diseases such as Duchenne muscular dystrophy, in which LOX and TGFβ signaling have been implicated and the balance between muscle constituents is disturbed.
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Liora
authors.initials: L
authors.lastname: Kutchuk
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90220, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Laitala
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-Bomgarten
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Pessia
authors.initials: P
authors.lastname: Shentzer
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90220, Finland.
authors.forename: Ann-Helen
authors.initials: AH
authors.lastname: Rosendahl
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: Eilot
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Moran
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
authors.affiliation: Biocenter Oulu and Department of Pathology, University of Oulu and Oulu University Hospital, Oulu 90220, Finland.
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90220, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
authors.affiliation: Oulu Center for Cell-Matrix Research, Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90220, Finland.
authors.forename: Joni M
authors.initials: JM
authors.lastname: Mäki
authors.affiliation: The Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa 31096, Israel phasson@tx.technion.ac.il.
authors.forename: Peleg
authors.initials: P
authors.lastname: Hasson
mesh_terms: D000818:Animals; D003238:Connective Tissue / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009132:Muscles / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D011247:Pregnancy; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; C077112:Lox protein, mouse; D008249:Protein-Lysine 6-Oxidase
keywords: Collagen; Lysyl oxidase; Mouse; Muscle; Muscle connective tissue; TGF-beta