Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

Autor: Volker Adams, T. Scott Bowen, Sarah Werner, Peggy Barthel, Christina Amberger, Anne Konzer, Johannes Graumann, Peter Sehr, Joe Lewis, Jan Provaznik, Vladimir Benes, Petra Büttner, Alexander Gasch, Norman Mangner, Christian C. Witt, Dittmar Labeit, Axel Linke, Siegfried Labeit
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Journal of Cachexia, Sarcopenia and Muscle, Vol 10, Iss 5, Pp 1102-1115 (2019)
Druh dokumentu: article
ISSN: 2190-6009
2190-5991
DOI: 10.1002/jcsm.12448
Popis: Abstract Background Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small‐molecule inhibitor of MuRF1 in treating CHF‐induced diaphragm myopathy and loss of contractile function. Methods Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham‐operated animals (sham) served as controls. One week post‐left anterior descending coronary artery ligation animals were randomized into two groups—one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946—a recently described MuRF1‐interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed. Results Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P
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