1. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program
- Author
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Morrison-Nozik, Alexander, Anand, Priti, Zhu, Han, Duan, Qiming, Sabeh, Mohamad, Prosdocimo, Domenick A, Lemieux, Madeleine E, Nordsborg, Nikolai, Russell, Aaron P, MacRae, Calum A, Gerber, Anthony N, Jain, Mukesh K, and Haldar, Saptarsi M
- Subjects
Medical Physiology ,Biomedical and Clinical Sciences ,Genetics ,Muscular Dystrophy ,Pediatric ,Rare Diseases ,Intellectual and Developmental Disabilities (IDD) ,Duchenne/ Becker Muscular Dystrophy ,Brain Disorders ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Musculoskeletal ,Animals ,Female ,Glucocorticoids ,Humans ,Kruppel-Like Transcription Factors ,Male ,Mice ,Mice ,Inbred C57BL ,Muscle ,Skeletal ,Muscular Dystrophy ,Duchenne ,Nuclear Proteins ,Receptors ,Glucocorticoid ,skeletal muscle metabolism ,glucocorticoid ,exercise ,Duchenne muscular dystrophy ,steroid hormone nuclear receptor - 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.
- Published
- 2015