title: Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity.
abstract: Following skeletal muscle injury, muscle stem cells (satellite cells) are activated, proliferate, and differentiate to form myofibers. We show that mRNA-decay protein AUF1 regulates satellite cell function through targeted degradation of specific mRNAs containing 3' AU-rich elements (AREs). auf1(-/-) mice undergo accelerated skeletal muscle wasting with age and impaired skeletal muscle repair following injury. Satellite cell mRNA analysis and regeneration studies demonstrate that auf1(-/-) satellite cell self-renewal is impaired due to increased stability and overexpression of ARE-mRNAs, including cell-autonomous overexpression of matrix metalloprotease MMP9. Secreted MMP9 degrades the skeletal muscle matrix, preventing satellite-cell-mediated regeneration and return to quiescence. Blocking MMP9 activity in auf1(-/-) mice restores skeletal muscle repair and maintenance of the satellite cell population. Control of ARE-mRNA decay by AUF1 represents a mechanism for adult stem cell regulation and is implicated in human skeletal muscle wasting diseases.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Devon M
authors.initials: DM
authors.lastname: Chenette
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Cadwallader
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA.
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Antwine
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Larkin
authors.affiliation: Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA. Electronic address: olwin@colorado.edu.
authors.forename: Bradley B
authors.initials: BB
authors.lastname: Olwin
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, USA. Electronic address: robert.schneider@nyumc.org.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D005260:Female; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism*; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C000630987:Hnrpd protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D020780:Matrix Metalloproteinase 9
keywords: AU-rich elements; AUF1; mRNA decay; muscle regeneration; muscle stem cells; satellite cells