title: The orphan nuclear receptor Nur77 is a determinant of myofiber size and muscle mass in mice.
abstract: We previously showed that the orphan nuclear receptor Nur77 (Nr4a1) plays an important role in the regulation of glucose homeostasis and oxidative metabolism in skeletal muscle. Here, we show using both gain- and loss-of-function models that Nur77 is also a regulator of muscle growth in mice. Transgenic expression of Nur77 in skeletal muscle in mice led to increases in myofiber size. Conversely, mice with global or muscle-specific deficiency in Nur77 exhibited reduced muscle mass and myofiber size. In contrast to Nur77 deficiency, deletion of the highly related nuclear receptor NOR1 (Nr4a3) had minimal effect on muscle mass and myofiber size. We further show that Nur77 mediates its effects on muscle size by orchestrating transcriptional programs that favor muscle growth, including the induction of insulin-like growth factor 1 (IGF1), as well as concomitant downregulation of growth-inhibitory genes, including myostatin, Fbxo32 (MAFbx), and Trim63 (MuRF1). Nur77-mediated increase in IGF1 led to activation of the Akt-mTOR-S6K cascade and the inhibition of FoxO3a activity. The dependence of Nur77 on IGF1 was recapitulated in primary myoblasts, establishing this as a cell-autonomous effect. Collectively, our findings identify Nur77 as a novel regulator of myofiber size and a potential transcriptional link between cellular metabolism and muscle growth.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.affiliation: The Division of Endocrinology, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Cortez-Toledo
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wroblewski
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: The Division of Endocrinology, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Lim
authors.affiliation: The Division of Endocrinology, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Carranza
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Orla
authors.initials: O
authors.lastname: Conneely
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104/INSERM U964/Université de Strasbourg, Collège de France, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA The Division of Endocrinology, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California, USA Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California USA lchao@chla.usc.edu.
authors.forename: Lily C
authors.identifier: http://orcid.org/0000-0002-6294-0589
authors.initials: LC
authors.lastname: Chao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D009154:Mutation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D000070584:Tripartite Motif Proteins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases