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Targeting MuRF1 by small molecules in a HFpEF rat model improves myocardial diastolic function and skeletal muscle contractility.
- Source :
-
Journal of cachexia, sarcopenia and muscle [J Cachexia Sarcopenia Muscle] 2022 Jun; Vol. 13 (3), pp. 1565-1581. Date of Electronic Publication: 2022 Mar 17. - Publication Year :
- 2022
-
Abstract
- Background: About half of heart failure (HF) patients, while having preserved left ventricular function, suffer from diastolic dysfunction (so-called 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-205) in HFpEF and to describe molecular changes elicited by MyoMed-205.<br />Methods: Twenty-week-old female obese ZSF1 rats received the MuRF1 inhibitor MyoMed-205 for 12 weeks; a comparison was made to age-matched untreated ZSF1-lean (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-wide analysis followed by WBs and RT-PCR was applied to identify specific genes and affected molecular pathways. MuRF1 knockout mice (MuRF1-KO) SKM tissues were included to validate MuRF1-specificity.<br />Results: By week 32, untreated obese rats had normal LV ejection fraction but augmented E/e' 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-205 treated rats had markedly improved diastolic function, less myocardial fibrosis, reduced SKM myopathy, and increased SKM function. SKM extracts from MyoMed-205 treated rats had reduced MuRF1 content and lowered total muscle protein ubiquitination. In addition, proteomic profiling identified eight proteins to respond specifically to MyoMed-205 treatment. Five out of these eight proteins are involved in mitochondrial metabolism, dynamics, or autophagy. Consistent with the mitochondria being a MyoMed-205 target, the synthesis of mitochondrial respiratory chain complexes I + II was increased in treated rats. MuRF1-KO SKM controls also had elevated mitochondrial complex I and II activities, also suggesting mitochondrial activity regulation by MuRF1.<br />Conclusions: MyoMed-205 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.<br /> (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)
- Subjects :
- Animals
Connectin metabolism
Diastole drug effects
Female
Fibrosis
Mice
Mice, Knockout
Muscular Atrophy drug therapy
Muscular Atrophy metabolism
Muscular Atrophy pathology
Myocardium pathology
Rats
Stroke Volume drug effects
Heart Failure drug therapy
Heart Failure metabolism
Heart Failure pathology
Muscle Proteins antagonists & inhibitors
Muscle Proteins metabolism
Muscle, Skeletal drug effects
Muscle, Skeletal metabolism
Small Molecule Libraries pharmacology
Tripartite Motif Proteins antagonists & inhibitors
Tripartite Motif Proteins metabolism
Ubiquitin-Protein Ligases antagonists & inhibitors
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2190-6009
- Volume :
- 13
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cachexia, sarcopenia and muscle
- Publication Type :
- Academic Journal
- Accession number :
- 35301823
- Full Text :
- https://doi.org/10.1002/jcsm.12968