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Mineralocorticoid Receptors: A Novel Therapeutic Target for Treating Duchenne Muscular Dystrophy

Chadwick, Jessica Ann
http://rave.ohiolink.edu/etdc/view?acc_num=osu1468946734

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Duchene 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 effect. 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. 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. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with the MR agonist aldosterone or antagonist spironolactone and identified 53 gene expression differences. Together these data support that MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases. However, the underlying mechanisms and functional role of MR activation in skeletal muscle is still unclear. Excessive MR activation is known to contribute to the pathogenesis of heart failure, presumably due to increased levels of its natural ligand aldosterone. However, clinical trials have shown that addition of an MR antagonist to standard-of-care regimens (ACE inhibitors) improves morbidity and mortality in patients, even when circulating aldosterone levels are within the physiological range. There is now a growing body of evidence that’s shown aldosterone, which was previously thought to only be synthesized in the adrenal cortex, can also be synthesized and metabolized locally in extra-adrenal tissues, including the heart, particularly in pathological states. We demonstrate for the first time that infiltrating immune cells clustered in damaged areas of dystrophic skeletal muscles have the capacity to produce the natural ligand of MR, aldosterone. Aldosterone synthase protein levels are increased in leukocytes isolated from dystrophic muscles compared with controls and local aldosterone levels in dystrophic skeletal muscles are increased, despite normal circulating levels. All of the genes encoding enzymes in the pathway required for aldosterone synthesis are expressed in muscle-derived leukocytes. 11ß-HSD2, the enzyme that inactivates glucocorticoids to increase MR selectivity for aldosterone, is also increased in dystrophic muscle tissue. These results, together with demonstrated preclinical efficacy of antagonists, suggest MR activation is in excess of physiological need, may contribute to the pathology of muscular dystrophy, and may have implications for other diseases with inflammation.
Jill Rafael-Fortney (Advisor)
277 p.
Biochemistry

Recommended Citations

Citations

  • Chadwick, J. A. (2016). Mineralocorticoid Receptors: A Novel Therapeutic Target for Treating Duchenne Muscular Dystrophy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468946734

    APA Style (7th edition)

  • Chadwick, Jessica. Mineralocorticoid Receptors: A Novel Therapeutic Target for Treating Duchenne Muscular Dystrophy . 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1468946734.

    MLA Style (8th edition)

  • Chadwick, Jessica. "Mineralocorticoid Receptors: A Novel Therapeutic Target for Treating Duchenne Muscular Dystrophy ." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1468946734

    Chicago Manual of Style (17th edition)

osu1468946734
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This open access ETD is published by The Ohio State University and OhioLINK.