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Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target
Author(s) -
Chadwick Jessica A.,
Hauck J. Spencer,
Lowe Jeovanna,
Shaw Jeremiah J.,
Guttridge Denis C.,
GomezSanchez Celso E.,
GomezSanchez Elise P.,
RafaelFortney Jill A.
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-276782
Subject(s) - spironolactone , skeletal muscle , lisinopril , mineralocorticoid receptor , endocrinology , medicine , myogenesis , myocyte , biology , duchenne muscular dystrophy , pharmacology , aldosterone , angiotensin converting enzyme , blood pressure
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‐type mice 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 (IC 50 0.1 nM) compared with untreated controls. Genes down‐regulated more than 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.— Chadwick, J. A., Hauck, J. S., Lowe, J., Shaw, J. J., Guttridge, D. C., Gomez‐Sanchez, C. E., Gomez‐Sanchez, E. P., Rafael‐Fortney, J. A. Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target. FASEB J. 29, 4544‐4554 (2015). www.fasebj.org