Mineralocorticoid Receptor Antagonists in Muscular Dystrophy Mice During Aging and Exercise
| Autor: | Feni K. Kadakia, Jill A. Rafael-Fortney, Neha Rastogi, Elise P. Gomez-Sanchez, Paul M.L. Janssen, Celso E. Gomez-Sanchez, Mohammad T. Elnakish, Kyle T. Floyd, Jonathan G. Zins, Jeovanna Lowe, Kyra K. Peczkowski, Michael J. Haupt |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Aging medicine.drug_class Duchenne muscular dystrophy Angiotensin-Converting Enzyme Inhibitors Spironolactone Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Mineralocorticoid receptor Internal medicine Physical Conditioning Animal medicine Animals Muscle Strength Muscular dystrophy Muscle Skeletal Mineralocorticoid Receptor Antagonists Inflammation Aldosterone biology business.industry Lisinopril Isoproterenol Angiotensin-converting enzyme Heart Adrenergic beta-Agonists medicine.disease Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology Endocrinology Neurology chemistry Mineralocorticoid biology.protein Mice Inbred mdx Neurology (clinical) Sedentary Behavior business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of neuromuscular diseases. 5(3) |
| ISSN: | 2214-3599 |
| Popis: | BACKGROUND: Mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors have shown pre-clinical efficacy for both skeletal and cardiac muscle outcomes in young sedentary dystrophin-deficient mdx mice also haploinsufficient for utrophin, a Duchenne muscular dystrophy (DMD) model. The mdx genotypic DMD model has mild pathology, making non-curative therapeutic effects difficult to distinguish at baseline. Since the cardiac benefit of miner-alocorticoid receptor antagonists has been translated to DMD patients, it is important to optimize potential advantages for skeletal muscle by further defining efficacy parameters. OBJECTIVE: We aimed to test whether therapeutic effects of mineralocorticoid receptor antagonists added to angiotensin converting enzyme inhibitors are detectable using three different reported methods of exacerbating the mdx phenotype. METHODS: We tested treatment with lisinopril and the mineralocorticoid receptor antagonist spironolactone in: 10 week-old exercised, 1 year-old sedentary, and 5 month-old isoproterenol treated mdx mice and performed comprehensive functional and histological measurements. RESULTS: None of the protocols to exacerbate mdx phenotypes resulted in dramatically enhanced pathology and no significant benefit was observed with treatment. CONCLUSIONS: Since endogenous mineralocorticoid aldosterone production from immune cells in dystrophic muscle may explain antagonist efficacy, it is likely that these drugs work optimally during the narrow window of peak inflammation in mdx mice. Exercised and aged mdx mice do not display prolific damage and inflammation, likely explaining the absence of continued efficacy of these drugs. Since inflammation is more prevalent in DMD patients, the therapeutic window for mineralocorticoid receptor antagonists in patients may be longer. |
| Databáze: | OpenAIRE |
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