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Functional analysis of cardiac‐specific loss of MuRF1 in diabetic cardiomyopathy
Author(s) -
Willis Monte S.,
Rajalingam Sahith,
Klüppel Michael
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06563
Subject(s) - diabetic cardiomyopathy , heart failure , medicine , endocrinology , cardiomyopathy , myocyte , diabetes mellitus , ubiquitin ligase , skeletal muscle , cardiology , ubiquitin , biology , biochemistry , gene
Diabetic cardiomyopathy is a serious complication in patients with type 2 diabetes, leading to pathological remodeling of the heart and a significantly increased risk of heart failure. Cardiovascular diseases are the leading cause of death in type 2 diabetes patients. The E3 ubiquitin ligase MuRF1 is expressed in heart and skeletal muscle, and we have shown that differential ubiquitination of target proteins by MuRF1 is of critical importance for the heart’s responses to atrophic and hypertrophic stimuli. In recent in vitro work, we showed that MuRF1 regulates cardiomyocyte metabolism by mono‐ubiquitination and subsequent nuclear export of PPARα, a master regulator of peroxisome function and fatty acid oxidation. These results suggest that MuRF1 plays a so far unknown role in heart metabolism and the progression of diabetic cardiomyopathy. However, any tissue‐specific roles of MuRF1 in heart versus skeletal muscle in‐vivo have not been experimentally addressed so far. To analyze the function of MuRF1 specifically in the heart during diabetic cardiomyopathy, we generated a mouse strain carrying a conditional and inducible loss‐of‐function mutation in MuRF1 via the introduction of loxP sites (MuRF1‐flox) and crossed these animals to transgenic animals expressing Cre recombinase under the control of the cardiomyocyte‐specific αMHC promoter (αMHC‐MerCreMer). Mice were treated with tamoxifen in chow for 7 days, followed by 21 days of chow. Subsequently, diabetic cardiomyopathy was induced by a 60% high fat diet (HFD) for 26 weeks, and disease progression was monitored by echocardiography, electrocardiography, glucose tolerance test and DEXA scans. Our preliminary data show that cardiac loss of MuRF1 can exacerbate cardiac deficits associated with diabetic cardiomyopathy. We will present data on our ongoing phenotypic analysis of these animals, and the elucidation of causative molecular mechanisms, including the effects on PPARα localization/activity and peroxisome function. This analysis will shed light on novel cardiac‐specific roles of MuRF1 in the context of diabetic cardiomyopathy, and potentially reveal new functions of cardiac MuRF1 in mediating crosstalk between heart and other tissues metabolically altered in diabetes, including skeletal muscle, liver, and adipose tissue. Support or Funding Information National Heart, Lung, and Blood Institute, R01HL104129