Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet
Date
2015-07
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
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.
Description
CITATION: Quintata, M. T. et al. 2015. Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet. BMC Endocrine Disorders, 15:36, doi:10.1186/s12902-015-0028-z.
The original publication is available at http://bmcendocrdisord.biomedcentral.com
The original publication is available at http://bmcendocrdisord.biomedcentral.com
Keywords
MuRF3, Diabetic cardiomyopathy, Post-translational modification, Multi-ubiquitin, PPAR, Ubiquitin ligase
Citation
Quintata, M. T. et al. 2015. Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet. BMC Endocrine Disorders, 15:36, doi:10.1186/s12902-015-0028-z.