期刊
FASEB JOURNAL
卷 29, 期 11, 页码 4544-4554出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.15-276782
关键词
aldosterone; gene expression microarray; muscular dystrophy; spironolactone; steroid hormone receptors
资金
- U.S. National Institutes of Health [R01 NS082868, R01 HL116533, T32 NS077984]
- Department of Defense [MD120063]
- Center for Muscle Health and Neuromuscular Disorders at The Ohio State University (OSU)
- Center for Muscle Health and Neuromuscular Disorders at Nationwide Children's Hospital
Early treatment with heart failure drugs lisinopril and spironolactone improves skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. The angiotensin converting enzyme inhibitor lisinopril and mineralocorticoid receptor (MR) antagonist spironolactone indirectly and directly target MR. The presence and function of MR in skeletal muscle have not been explored. MR mRNA and protein are present in all tested skeletal muscles from both wild-typemice and DMD mouse models. MR expression is cell autonomous in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with MR agonist (aldosterone; EC50 1.3 nM) or antagonist (spironolactone; IC50 1.6 nM), and 53 gene expression differences were identified. Five differences were conserved in quadriceps muscles from dystrophic mice treated with spironolactone plus lisinopril (IC50 0.1 nM) compared with untreated controls. Genes down-regulated morethan 2-fold by MR antagonism included FOS, ANKRD1, and GADD45B, with known roles in skeletal muscle, in addition to NPR3 and SERPINA3, bona fide targets of MR in other tissues. MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases.
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