Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Alexander Morrison-Nozik; Priti Anand; Han Zhu; Qiming Duan; Mohamad Sabeh; Domenick A Prosdocimo; Madeleine E Lemieux; Nikolai Baastrup Nordsborg; Aaron P Russell; Calum A MacRae; Anthony N Gerber; Mukesh K Jain; Saptarsi M Haldar

doi:10.1073/pnas.1512968112

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Alexander Morrison-Nozik, Priti Anand, Han Zhu, Qiming Duan, Mohamad Sabeh, Domenick A Prosdocimo, Madeleine E Lemieux, Nikolai Baastrup Nordsborg, Aaron P Russell, Calum A MacRae, Anthony N Gerber, Mukesh K Jain, Saptarsi M Haldar

The August Krogh Section for Human Physiology

40 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	112
Issue number	49
Pages (from-to)	E6780-E6789
Number of pages	10
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1512968112
Publication status	Published - 8 Dec 2015

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Morrison-Nozik, A., Anand, P., Zhu, H., Duan, Q., Sabeh, M., Prosdocimo, D. A., Lemieux, M. E., Nordsborg, N. B., Russell, A. P., MacRae, C. A., Gerber, A. N., Jain, M. K., & Haldar, S. M. (2015). Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program. Proceedings of the National Academy of Sciences of the United States of America, 112(49), E6780-E6789. https://doi.org/10.1073/pnas.1512968112

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program. / Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 49, 08.12.2015, p. E6780-E6789.

Research output: Contribution to journal › Journal article › Research › peer-review

Morrison-Nozik, A, Anand, P, Zhu, H, Duan, Q, Sabeh, M, Prosdocimo, DA, Lemieux, ME, Nordsborg, NB, Russell, AP, MacRae, CA, Gerber, AN, Jain, MK & Haldar, SM 2015, 'Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 49, pp. E6780-E6789. https://doi.org/10.1073/pnas.1512968112

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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.",

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AU - Sabeh, Mohamad

AU - Prosdocimo, Domenick A

AU - Lemieux, Madeleine E

AU - Nordsborg, Nikolai Baastrup

AU - Russell, Aaron P

AU - MacRae, Calum A

AU - Gerber, Anthony N

AU - Jain, Mukesh K

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AB - 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.

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Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

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