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

Quintana, MT and He, J and Sullivan, J and Grevengoed, T and Schisler, J and Han, Y and Hill, JA and Yates, CC and Stansfield, WE and Mapanga, RF and Essop, MF and Muehlbauer, MJ and Newgard, CB and Bain, JR and Willis, MS (2015) Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet. BMC Endocrine Disorders, 15 (1).

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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.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Quintana, MT
He, J
Sullivan, J
Grevengoed, T
Schisler, J
Han, Y
Hill, JA
Yates, CC
Stansfield, WE
Mapanga, RF
Essop, MF
Muehlbauer, MJ
Newgard, CB
Bain, JR
Willis, MS
Date: 12 December 2015
Date Type: Publication
Journal or Publication Title: BMC Endocrine Disorders
Volume: 15
Number: 1
DOI or Unique Handle: 10.1186/s12902-015-0028-z
Schools and Programs: School of Nursing > Nursing
Refereed: Yes
Date Deposited: 17 Aug 2016 13:48
Last Modified: 30 Mar 2021 11:55
URI: http://d-scholarship.pitt.edu/id/eprint/29224

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