title: Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program.
abstract: Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Alexander
authors.initials: A
authors.lastname: Morrison-Nozik
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Gladstone Institutes, San Francisco, CA 94158;
authors.forename: Priti
authors.initials: P
authors.lastname: Anand
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Han
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Gladstone Institutes, San Francisco, CA 94158;
authors.forename: Qiming
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH 44106;
authors.forename: Mohamad
authors.initials: M
authors.lastname: Sabeh
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Domenick A
authors.initials: DA
authors.lastname: Prosdocimo
authors.affiliation: Bioinfo, Plantagenet, Ontario, Canada K0B IL0;
authors.forename: Madeleine E
authors.identifier: http://orcid.org/0000-0001-6355-8691
authors.initials: ME
authors.lastname: Lemieux
authors.affiliation: Department of Nutrition, Exercise and Sports Sciences, University of Copenhagen, DK-200 Copenhagen, Denmark;
authors.forename: Nikolai
authors.initials: N
authors.lastname: Nordsborg
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Science, Deakin University, Burwood, VIC 3125, Australia;
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Cardiovascular Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115;
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: Department of Pulmonary Medicine, National Jewish Health and University of Colorado Denver School of Medicine, Denver, CO 80206;
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Gerber
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH 44106;
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.affiliation: Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; Gladstone Institutes, San Francisco, CA 94158; Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH 44106; Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, CA 94158 saptarsi.haldar@gladstone.ucsf.edu.
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
mesh_terms: D000818:Animals; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology
chemical_list: D005938:Glucocorticoids; C414172:KLF15 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid
keywords: Duchenne muscular dystrophy; exercise; glucocorticoid; skeletal muscle metabolism; steroid hormone nuclear receptor