MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet
Date
2015
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Background: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents
an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy
involves the enhanced activation of PPAR transcription factors, including PPARα, and to a lesser degree
PPARβ and PPARγ1. How these transcription factors are regulated in the heart is largely unknown. Recent studies have
described post-translational ubiquitination of PPARs as ways in which PPAR activity is inhibited in cancer. However,
specific mechanisms in the heart have not previously been described. Recent studies have implicated the musclespecific
ubiquitin ligase muscle ring finger-2 (MuRF2) in inhibiting the nuclear transcription factor SRF. Initial studies of
MuRF2−/− hearts revealed enhanced PPAR activity, leading to the hypothesis that MuRF2 regulates PPAR activity by
post-translational ubiquitination.
Methods: MuRF2−/− mice were challenged with a 26-week 60% fat diet designed to simulate obesity-mediated
insulin resistance and diabetic cardiomyopathy. Mice were followed by conscious echocardiography, blood glucose,
tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics,
and PPARα, PPARβ, and PPARγ1-regulated mRNA expression.
Results: MuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high
fat diet. Compared to littermate wildtype hearts, MuRF2−/− hearts exhibit an exaggerated diabetic cardiomyopathy,
characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2−/−
hearts had significantly increased PPARα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2’s
regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARα and PPARγ1
in vitro, consistent with its non-degradatory role in diabetic cardiomyopathy. However, increasing MuRF2:PPARγ1
(>5:1) beyond physiological levels drove poly-ubiquitin-mediated degradation of PPARγ1 in vitro, indicating large
MuRF2 increases may lead to PPAR degradation if found in other disease states.
Conclusions: Mutations in MuRF2 have been described to contribute to the severity of familial hypertrophic cardiomyopathy.
The present study suggests that the lack of MuRF2, as found in these patients, can result in an exaggerated
diabetic cardiomyopathy. These studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARα and
PPARγ1 activities in vivo via post-translational modification without degradation.
Description
CITATION: He, J., et al. 2015. MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet. Cardiovascular Diabetology, 14:97, doi:10.1186/s12933-015-0252-x.
The original publication is available at http://cardiab.biomedcentral.com
The original publication is available at http://cardiab.biomedcentral.com
Keywords
Cardiovascular disease, Diabetes mellitus, Diabetic cardiomyopathy, Muscle ring finger-2 (MuRF2)
Citation
He, J., et al. 2015. MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet. Cardiovascular Diabetology, 14:97, doi:10.1186/s12933-015-0252-x