Talk abstracts
Talk on Wednesday 04:30-04:45pm submitted by Jessica Chadwick
Mineralocorticoid Receptors in Skeletal Muscle are a Potential Therapeutic Target for Duchenne Muscular Dystrophy
Jessica Chadwick (Dept. of Molecular & Cellular Biochemistry, & Dept. of Physiology & Cell Biology, College of Medicine, The Ohio State University), James Hauck (Dept. of Molecular & Cellular Biochemistry, & Dept. of Physiology & Cell Biology, College of Medicine, The Ohio State University), Jeovanna Lowe (Dept. of Molecular & Cellular Biochemistry, & Dept. of Physiology & Cell Biology, College of Medicine, The Ohio State University), Denis Guttridge (Department of Mol. Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University), Jill Rafael-Fortney (Dept. of Molecular & Cellular Biochemistry, & Dept. of Physiology & Cell Biology, College of Medicine, The Ohio State University)
Abstract:
Duchenne muscular dystrophy (DMD) is a progressive and fatal degenerative disease, affecting around 1 in 3,600 boys. Glucocorticoids (glucocorticoid receptor agonists), the current standard-of-care treatment, defer severity of some symptoms and prolong mobility an average of 2 years. However, these drugs do not exhibit long term efficacy and have numerous deleterious side effects. Our lab has identified a potential new treatment for DMD using the mineralocorticoid receptor (MR) antagonist spironolactone and angiotensin converting enzyme inhibitor lisinopril. Preclinical 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. Both spironolactone and lisinopril target the mineralocorticoid receptor (directly and indirectly, respectively), however very little is known about the role of MR in the context of skeletal muscle. Despite long-standing clinical use of MR antagonists in cardiology, only serpina-3 has recently been validated as a bona-fide downstream target in cardiomyocytes. We show MR is present in a wide variety of normal and dystrophic mouse skeletal muscles. We confirm MR is expressed in a cell autonomous manner in skeletal muscle using the C2C12 mouse cell line and human primary undifferentiated and differentiated myogenic cultures. Several genes with known roles in striated muscle are deferentially expressed between quadriceps muscles from untreated and spironolactone + lisinopril treated het mice. We demonstrate that many of the corresponding proteins vary in abundance or localization between normal and dystrophic muscles. A subset of the in-vivo gene expression changes were identified when comparing normal human primary myogenic cultures treated with an MR agonist or antagonist, including the one known MR target in heart (serpina-3). These genes represent potential direct MR downstream targets, which may help elucidate the mechanism behind the efficacy of these drugs and serve as biomarkers of treatment.
References:
Population frequencies of inherited neuromuscular diseases-a world survey.
A.E. Emery
Prednisone treatment in Duchenne muscular dystrophy. Long-term benefit.
S. DeSilva, D.B. Drachman, D. Mellits and R.W. Kuncl
Contrasting effects of steroids and angiotensin-converting enzyme inhibitors in a mouse model of dystrophin-deficient cardiomyopathy.
R. Bauer, V. Straub, A. Blain, K. Bushby and G.A. MacGowan
Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy.
C. Angelini and E. Peterle
Early Treatment with Lisinopril and Spironolactone Preserves Cardiac and Skeletal Muscle in Duchenne Muscular Dystrophy Mice.
J.A Rafael-Fortney et al.
Molecular signature of mineralocorticoid receptor signaling in cardiomyocytes: from cultured cells to mouse heart.
C. Latouche et al.
Keywords: muscular dystrophy , mineralocorticoid receptor , skeletal muscle