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

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dc.contributor.authorQuintana, Megan T.en_ZA
dc.contributor.authorHe, Junen_ZA
dc.contributor.authorSullivan, Jenythen_ZA
dc.contributor.authorGrevengoed, Trishaen_ZA
dc.contributor.authorSchisler, Jonathanen_ZA
dc.contributor.authorHan, Yipinen_ZA
dc.contributor.authorHill, Joseph A.en_ZA
dc.contributor.authorYates, Cecelia C.en_ZA
dc.contributor.authorStansfield, William E.en_ZA
dc.contributor.authorMapanga, Rudo F.en_ZA
dc.contributor.authorEssop, M. Faadielen_ZA
dc.contributor.authorMuehlbauer, Michael J.en_ZA
dc.contributor.authorNewgard, Christopher B.en_ZA
dc.contributor.authorBain, James R.en_ZA
dc.contributor.authorWillis, Monte S.en_ZA
dc.date.accessioned2016-11-01T06:48:31Z
dc.date.available2016-11-01T06:48:31Z
dc.date.issued2015-07
dc.descriptionCITATION: 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.
dc.descriptionThe original publication is available at http://bmcendocrdisord.biomedcentral.com
dc.description.abstractBackground: 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.en_ZA
dc.description.urihttp://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-015-0028-z
dc.description.versionPublisher's version
dc.format.extent18 pages : illustrations
dc.identifier.citationQuintata, 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.
dc.identifier.issn1472-6823 (online)
dc.identifier.otherdoi:10.1186/s12902-015-0028-z
dc.identifier.urihttp://hdl.handle.net/10019.1/99787
dc.language.isoen_ZAen_ZA
dc.publisherBioMed Central
dc.rights.holderAuthors retain copyright
dc.subjectMuRF3en_ZA
dc.subjectDiabetic cardiomyopathyen_ZA
dc.subjectPost-translational modificationen_ZA
dc.subjectMulti-ubiquitinen_ZA
dc.subjectPPARen_ZA
dc.subjectUbiquitin ligaseen_ZA
dc.titleMuscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat dieten_ZA
dc.typeArticleen_ZA
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