文章基本信息

标题：Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program
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作者：Alexander Morrison-Nozik ; Priti Anand ; Han Zhu 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：49
页码：E6780-E6789
DOI：10.1073/pnas.1512968112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceClassic physiological studies have documented the endurance-promoting effects of glucocorticoid (GC) hormones on skeletal muscle. Pharmacologic GC therapy also improves muscle function in patients with Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. Despite these well-established physiological and clinical observations, the molecular basis underlying the beneficial effects of GCs in skeletal muscle remains obscure. This study shows that physiological effects of GCs on muscle endurance and their therapeutic effect in DMD are mediated, in part, via activation of a potent metabolic gene called Kruppel-like factor 15 (KLF15). Importantly, KLF15 does not drive GC-mediated muscle wasting. These data shed light on the poorly understood ergogenic properties of GCs, findings that may inform steroid-sparing therapies for DMD and other muscle diseases. 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.
关键词：skeletal muscle metabolism ; glucocorticoid ; exercise ; Duchenne muscular dystrophy ; steroid hormone nuclear receptor