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BMC Endocrine Disorders
Published in: BMC Endocrine Disorders 1/2015

Open Access 01-12-2015 | Research article

Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet

Authors: Megan T. Quintana, Jun He, Jenyth Sullivan, Trisha Grevengoed, Jonathan Schisler, Yipin Han, Joseph A. Hill, Cecelia C. Yates, William E. Stansfield, Rudo F. Mapanga, M. Faadiel Essop, Michael J. Muehlbauer, Christopher B. Newgard, James R. Bain, Monte S. Willis

Published in: BMC Endocrine Disorders | Issue 1/2015

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Abstract

Background

The pathogenesis of diabetic cardiomyopathy (DCM) involves the enhanced activation of peroxisome proliferator activating receptor (PPAR) transcription factors, including the most prominent isoform in the heart, PPARα. In cancer cells and adipocytes, post-translational modification of PPARs have been identified, including ligand-dependent degradation of PPARs by specific ubiquitin ligases. However, the regulation of PPARs in cardiomyocytes and heart have not previously been identified. We recently identified that muscle ring finger-1 (MuRF1) and MuRF2 differentially inhibit PPAR activities by mono-ubiquitination, leading to the hypothesis that MuRF3 may regulate PPAR activity in vivo to regulate DCM.

Methods

MuRF3−/− mice were challenged with 26 weeks 60 % high fat diet to induce insulin resistance and DCM. Conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARβ, and PPARγ1 activities were assayed.

Results

MuRF3−/− mice exhibited a premature systolic heart failure by 6 weeks high fat diet (vs. 12 weeks in MuRF3+/+). MuRF3−/− mice weighed significantly less than sibling-matched wildtype mice after 26 weeks HFD. These differences may be largely due to resistance to fat accumulation, as MRI analysis revealed MuRF3−/− mice had significantly less fat mass, but not lean body mass. In vitro ubiquitination assays identified MuRF3 mono-ubiquitinated PPARα and PPARγ1, but not PPARβ.

Conclusions

These findings suggest that MuRF3 helps stabilize cardiac PPARα and PPARγ1 in vivo to support resistance to the development of DCM.
MuRF3 also plays an unexpected role in regulating fat storage despite being found only in striated muscle.
Appendix
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Metadata
Title
Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet
Authors
Megan T. Quintana
Jun He
Jenyth Sullivan
Trisha Grevengoed
Jonathan Schisler
Yipin Han
Joseph A. Hill
Cecelia C. Yates
William E. Stansfield
Rudo F. Mapanga
M. Faadiel Essop
Michael J. Muehlbauer
Christopher B. Newgard
James R. Bain
Monte S. Willis
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Endocrine Disorders / Issue 1/2015
Electronic ISSN: 1472-6823
DOI
https://doi.org/10.1186/s12902-015-0028-z

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