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

BMC Endocrine Disorders

Monte S. Willis^1,11  James R. Bain³  Christopher B. Newgard³  Michael J. Muehlbauer^1,12  M. Faadiel Essop⁹  Rudo F. Mapanga⁹  William E. Stansfield¹  Cecelia C. Yates⁴  Joseph A. Hill⁶  Yipin Han⁷  Jonathan Schisler^1,10  Trisha Grevengoed⁵  Jenyth Sullivan²  Jun He⁸  Megan T. Quintana¹ 

[1] Department of Surgery, University of North Carolina, Chapel Hill, NC, USA;Department of Biology, University of North Carolina, Chapel Hill, NC, USA;Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA;Department of Health Promotions and Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA;Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA;Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA;North Carolina State University, Department of Engineering, Raleigh, NC, USA;General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China;Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch 7600, South Africa;Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA;McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA;Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA

关键词: Ubiquitin ligase;    PPAR;    Multi-ubiquitin;    Post-translational modification;    Diabetic cardiomyopathy;    MuRF3;   

Others  :  1221186
DOI  :  10.1186/s12902-015-0028-z

 received in 2015-04-02, accepted in 2015-06-01,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Quintana et al.

【 图 表 】

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