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Elucidating the Role of Mineralocorticoid Receptors in Skeletal Muscle as a Potential Therapeutic Target for Duchenne Muscular Dystrophy
Author(s) -
Chadwick Jessica,
Hauck James,
Lowe Jeovanna,
RafaelFortney Jill
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/fasebj.29.1_supplement.1038.2
Subject(s) - duchenne muscular dystrophy , skeletal muscle , endocrinology , medicine , mineralocorticoid receptor , muscular dystrophy , biology , myocyte , itga7 , myopathy , utrophin , dystrophin , aldosterone
Our lab identified a potential new treatment for Duchenne Muscular Dystrophy using the mineralocorticoid receptor (MR) antagonist spironolactone and ACE inhibitor lisinopril. Drug studies using dystrophic Het ( utrn +/‐ ;mdx ) mice showed a dramatic improvement in both respiratory and limb muscle force and a reduction of ongoing muscle damage, in addition to preventing cardiomyopathy. We show MR is present in both skeletal muscle tissue and myogenic cultures,supporting a direct affect by MR antagonists on skeletal muscle. Global analysis of gene expression between treated and untreated dystrophic mice identified potential molecular targets to unravel the drugs' mode of action. Preliminary microarray data comparing quadriceps muscle from lisinopril and spironolactone treated het mice to untreated controls revealed changes in the expression of several gene targets with known roles in striated muscle,Gene Name Gene Symbol Fold‐change (Treated/Control) Role in Striated Muscleankyrin repeat domain 1 Ankrd1 ‐2.15634 Marker of skeletal muscle pathological remodeling tight junction protein 2 Tjp2 ‐2.02372 Important molecular target in vascular remodeling myosin VA Myo5a ‐2.12497 Involved in maturation of NMJs in regenerating muscle mid1 interacting protein 1 Mid1ip1 ‐2.48061 Potential biomarker of skeletal myopathy myosin binding protein H Mybph 2.059236 Muscle remodeling in response to injury thyroid hormone responsive SPOT14 homolog Thrsp 2.138901 Modulator of fatty acid synthesiswhich have been confirmed using immunofluorescence and western blot analysis. Myogenic cultures treated with MR agonists and antagonists are being used to test whether these potential downstream targets are affected in a cell autologous manner in skeletal muscle and represent bona fide MR gene targets. NIH 1 R01 NS082868; T32 NS077984