title: Extracellular deposition of matrilin-2 controls the timing of the myogenic program during muscle regeneration.
abstract: Here, we identify a role for the matrilin-2 (Matn2) extracellular matrix protein in controlling the early stages of myogenic differentiation. We observed Matn2 deposition around proliferating, differentiating and fusing myoblasts in culture and during muscle regeneration in vivo. Silencing of Matn2 delayed the expression of the Cdk inhibitor p21 and of the myogenic genes Nfix, MyoD and Myog, explaining the retarded cell cycle exit and myoblast differentiation. Rescue of Matn2 expression restored differentiation and the expression of p21 and of the myogenic genes. TGF-β1 inhibited myogenic differentiation at least in part by repressing Matn2 expression, which inhibited the onset of a positive-feedback loop whereby Matn2 and Nfix activate the expression of one another and activate myoblast differentiation. In vivo, myoblast cell cycle arrest and muscle regeneration was delayed in Matn2(-/-) relative to wild-type mice. The expression levels of Trf3 and myogenic genes were robustly reduced in Matn2(-/-) fetal limbs and in differentiating primary myoblast cultures, establishing Matn2 as a key modulator of the regulatory cascade that initiates terminal myogenic differentiation. Our data thus identify Matn2 as a crucial component of a genetic switch that modulates the onset of tissue repair.
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Deák
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary mates@brc.hu kiss@brc.hu.
authors.forename: Lajos
authors.initials: L
authors.lastname: Mátés
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary Institute of Physiological Chemistry and Pathobiochemistry, Muenster University, D-48149 Muenster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Korpos
authors.affiliation: Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary.
authors.forename: Agnes
authors.initials: A
authors.lastname: Zvara
authors.affiliation: Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Szénási
authors.affiliation: Institute of Biochemistry, Faculty of General Medicine, University of Szeged, H-6720 Szeged, Hungary Department of Biochemistry and Molecular Biology, Faculty of Natural Sciences and Informatics, University of Szeged, H-6720 Szeged, Hungary.
authors.forename: Mónika
authors.initials: M
authors.lastname: Kiricsi
authors.affiliation: Institute of Biochemistry, Faculty of General Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors.forename: Luca
authors.initials: L
authors.lastname: Mendler
authors.affiliation: Institute of Biochemistry, Faculty of General Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors.forename: Anikó
authors.initials: A
authors.lastname: Keller-Pintér
authors.affiliation: Avidin Ltd., H-6726 Szeged, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Ozsvári
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary.
authors.forename: Hajnalka
authors.initials: H
authors.lastname: Juhász
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Muenster University, D-48149 Muenster, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Sorokin
authors.affiliation: Institute of Biochemistry, Faculty of General Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Dux
authors.affiliation: Institute of Biotechnology, University of Lausanne, and Center for Biotechnology of the University of Lausanne and École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mermod
authors.affiliation: Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary Avidin Ltd., H-6726 Szeged, Hungary.
authors.forename: László G
authors.initials: LG
authors.lastname: Puskás
authors.affiliation: Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6701 Szeged, Hungary Avidin Ltd., H-6726 Szeged, Hungary mates@brc.hu kiss@brc.hu.
authors.forename: Ibolya
authors.initials: I
authors.lastname: Kiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D004546:Elapid Venoms / Q000008:administration & dosage; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D064235:Matrilin Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics; D009132:Muscles / Q000473:pathology / Q000502:physiology*; D032446:Myoblasts / Q000502:physiology*; D009336:Necrosis / Q000139:chemically induced / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000235:genetics; D013997:Time Factors
chemical_list: D004546:Elapid Venoms; D064235:Matrilin Proteins; C005082:notexin
keywords: BMP signaling; Matn2 shRNA; Muscle regeneration; Myogenesis; NFI; TGF-β signaling; Trf3