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: Alexander Morrison-Nozik, Priti Anand, Han Zhu, Qiming Duan, Mohamad Sabeh, Domenick A Prosdocimo, Madeleine E Lemieux, Nikolai Nordsborg, Aaron P Russell, Calum A MacRae, Anthony N Gerber, Mukesh K Jain, Saptarsi M Haldar
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 49 Pg. E6780-9 (Dec 08 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26598680 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucocorticoids
• KLF15 protein, human
• Kruppel-Like Transcription Factors
• Nuclear Proteins
• Receptors, Glucocorticoid

Topics

• Animals
• Female
• Glucocorticoids (pharmacology, therapeutic use)
• Humans
• Kruppel-Like Transcription Factors (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Skeletal (drug effects, physiopathology)
• Muscular Dystrophy, Duchenne (drug therapy)
• Nuclear Proteins (physiology)
• Receptors, Glucocorticoid (physiology)