title: MicroRNA-29a in Adult Muscle Stem Cells Controls Skeletal Muscle Regeneration During Injury and Exercise Downstream of Fibroblast Growth Factor-2.
abstract: The expansion of myogenic progenitors (MPs) in the adult muscle stem cell niche is critical for the regeneration of skeletal muscle. Activation of quiescent MPs depends on the dismantling of the basement membrane and increased access to growth factors such as fibroblast growth factor-2 (FGF2). Here, we demonstrate using microRNA (miRNA) profiling in mouse and human myoblasts that the capacity of FGF2 to stimulate myoblast proliferation is mediated by miR-29a. FGF2 induces miR-29a expression and inhibition of miR-29a using pharmacological or genetic deletion decreases myoblast proliferation. Next generation RNA sequencing from miR-29a knockout myoblasts (Pax7(CE/+) ; miR-29a(flox/flox) ) identified members of the basement membrane as the most abundant miR-29a targets. Using gain- and loss-of-function experiments, we confirm that miR-29a coordinately regulates Fbn1, Lamc1, Nid2, Col4a1, Hspg2 and Sparc in myoblasts in vitro and in MPs in vivo. Induction of FGF2 and miR-29a and downregulation of its target genes precedes muscle regeneration during cardiotoxin (CTX)-induced muscle injury. Importantly, MP-specific tamoxifen-induced deletion of miR-29a in adult skeletal muscle decreased the proliferation and formation of newly formed myofibers during both CTX-induced muscle injury and after a single bout of eccentric exercise. Our results identify a novel miRNA-based checkpoint of the basement membrane in the adult muscle stem cell niche. Strategies targeting miR-29a might provide useful clinical approaches to maintain muscle mass in disease states such as ageing that involve aberrant FGF2 signaling.
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University Zurich and University Hospital Zurich, Zurich, Switzerland.|Competence Center Personalized Medicine, ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Artur
authors.initials: A
authors.lastname: Galimov
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Troy L
authors.initials: TL
authors.lastname: Merry
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University Zurich and University Hospital Zurich, Zurich, Switzerland.
authors.forename: Edlira
authors.initials: E
authors.lastname: Luca
authors.affiliation: Institute of Neuropathology, University Zurich and University Hospital Zurich, Zurich, Switzerland.
authors.forename: Elisabeth J
authors.initials: EJ
authors.lastname: Rushing
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University Zurich and University Hospital Zurich, Zurich, Switzerland.|Competence Center Personalized Medicine, ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Amir
authors.initials: A
authors.lastname: Mizbani
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University Zurich and University Hospital Zurich, Zurich, Switzerland.|Competence Center Personalized Medicine, ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Katarina
authors.initials: K
authors.lastname: Turcekova
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University Zurich and University Hospital Zurich, Zurich, Switzerland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Hartung
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Competence Center Personalized Medicine, ETH Zurich and University of Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Ristow
authors.affiliation: Division of Endocrinology, Diabetes, and Clinical Nutrition, University Zurich and University Hospital Zurich, Zurich, Switzerland.|Competence Center Personalized Medicine, ETH Zurich and University of Zurich, Zurich, Switzerland.|Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Krützfeldt
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000166:cytology / Q000254:growth & development; D012038:Regeneration; D014945:Wound Healing / Q000235:genetics
chemical_list: C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016222:Fibroblast Growth Factor 2
keywords: Basement membrane; Exercise; FGF2; MicroRNA; Regeneration; Skeletal muscle