{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:43:03Z","timestamp":1790775783354,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T00:00:00Z","timestamp":1647475200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001674","name":"Fondation Leducq","doi-asserted-by":"publisher","award":["13CVD04"],"award-info":[{"award-number":["13CVD04"]}],"id":[{"id":"10.13039\/501100001674","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so\u2010called HFpEF). No specific therapeutics are available for HFpEF in contrast to HF where reduced ejection fractions (HFrEF) can be treated pharmacologically. Myocardial titin filament stiffening, endothelial dysfunction, and skeletal muscle (SKM) myopathy are suspected to contribute to HFpEF genesis. We previously described small molecules interfering with MuRF1 target recognition thereby attenuating SKM myopathy and dysfunction in HFrEF animal models. The aim of the present study was to test the efficacy of one small molecule (MyoMed\u2010205) in HFpEF and to describe molecular changes elicited by MyoMed\u2010205.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twenty\u2010week\u2010old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed\u2010205 for 12\u00a0weeks; a comparison was made to age\u2010matched untreated ZSF1\u2010lean (healthy) and obese rats as controls. LV (left ventricle) function was assessed by echocardiography and by invasive haemodynamic measurements until week 32. At week 32, SKM and endothelial functions were measured and tissues collected for molecular analyses. Proteome\u2010wide analysis followed by WBs and RT\u2010PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1\u2010KO) SKM tissues were included to validate MuRF1\u2010specificity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>By week 32, untreated obese rats had normal LV ejection fraction but augmented E\/e\u2032 ratios and increased end diastolic pressure and myocardial fibrosis, all typical features of HFpEF. Furthermore, SKM myopathy (both atrophy and force loss) and endothelial dysfunction were detected. In contrast, MyoMed\u2010205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed\u2010205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed\u2010205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed\u2010205 target, the synthesis of mitochondrial respiratory chain complexes I\u00a0+\u00a0II was increased in treated rats. MuRF1\u2010KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>MyoMed\u2010205 improved myocardial diastolic function and prevented SKM atrophy\/function in the ZSF1 animal model of HFpEF. Mechanistically, SKM benefited from an attenuated ubiquitin proteasome system and augmented synthesis\/activity of proteins of the mitochondrial respiratory chain while the myocardium seemed to benefit from reduced titin modifications and fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12968","type":"journal-article","created":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T03:39:49Z","timestamp":1647574789000},"page":"1565-1581","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7955-7324","authenticated-orcid":false,"given":"Volker","family":"Adams","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology TU Dresden, Heart Center Dresden  Dresden 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and Experimental Cardiology TU Dresden, Heart Center Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anett","family":"Jannasch","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery TU Dresden, Heart Center Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Goto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology TU Dresden, Heart Center Dresden  Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Lyall","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"M\u00e4nnel","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology TU Dresden, Heart Center Dresden  Dresden 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