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.. Small-molecule mediated chemical knock-down of MuRF1/2 and attenuation of diaphragm dysfunction in chronic heart failure

Background: Chronic heart failure (CHF) leads to diaphragm myopathy thatsignificantly impairs quality of life and worsens prognosis. In this study, we aimed toassess the efficacy of a recently discovered small-molecule inhibitor of MuRF1 intreating CHF-induced diaphragm myopathy and loss of contractile function.Methods: Myocardial infarction was induced in mice by ligation of the left anteriordescending coronary artery (LAD). Sham operated animals (sham) served as controls.One week post-LAD ligation animals were randomized into 2 groups – one group wasfed control rodent chow, whereas the other group was fed a diet containing 0.1% of thecompound ID#704946 - a recently described MuRF1 interfering small molecule.Echocardiography confirmed development of CHF after 10 weeks. Functional andmolecular analysis of the diaphragm (DIA) was subsequently performed.Results: CHF induced diaphragm fiber atrophy and contractile dysfunction by ~20%, aswell as decreased activity of enzymes involved in mitochondrial energy production(P<0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects onthe diaphragm: contractile function was protected, while mitochondrial enzyme activityand upregulation of the MuRF1and MuRF2 were attenuated after infarct.Conclusions: Our murine CHF model presented with diaphragm fiber atrophy, impairedcontractile function, and reduced mitochondrial enzyme activities. ID#704946 rescuedfrom this partially, possibly by targeting MuRF1/2. However, at this stage of our study,we refrain to claim specific mechanism(s) and targets of ID#704946, because thenature of changes after 12 weeks of feeding are likely to be complex and are notnecessarily caused by direct mechanistic effects.