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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Endocrine Disorders 1/2015

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

Zeitschrift:
BMC Endocrine Disorders > Ausgabe 1/2015
Autoren:
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12902-015-0028-z) contains supplementary material, which is available to authorized users.
Megan T. Quintana and Jun He contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MQ, J He, J Hill, and MW conceived the experimental approach, coordinated and performed the animal experiments (husbandry, feeding, breeding, colony management). JH, MQ performed western blots, blood collection and insulin analyses in addition to molecular in vitro tests. MW and MQ performed the echocardiography and harvested the tissues for metabolomics. JH, J Schisler, and WS assisted with the design of the high fat diet and interpretation of the cardiac function and morphometric data. YH performed DNA genotyping of the mouse colony to confirm identification after harvesting and contributed to analysis and interpretation of molecular studies. J Sullivan and TG performed and assisted J He and MQ with determining glycogen and triglyceride levels in skeletal muscle, liver, and heart. CY performed histological analysis of fibrosis and vimentin staining. RM and MFE designed the O-Glc-NAC studies, performed the immunoblots, and wrote the interpretation of the results. JB, CN, and MM performed the non-targeted metabolomics studies and identified the peaks; MW performed the Metaboanalyst presentation and interpretation of the metabolomics results. MW, MQ, and JH designed, performed, and interpreted experiments delineating MuRF3’s post-translational modification of PPAR isoforms. All authors read and approved the final manuscript.

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.
Zusatzmaterial
Additional file 1: Figure S1. Analysis of circulating total cholesterol and triglyceride and histology in MuRF3−/− mice after high fat diet. A. Representative H&E analysis of MuRF2−/− and MuRF2+/+ tissue. B. Fasting total cholesterol and fasting serum triglyceride levels. C. Organ weights at 26 weeks high fat diet of gastrocnemius, soleus, and tibialis anterior. Values represent the mean ± SE (N indicated in bars). Values expressed as Mean ± SE. A one-way ANOVA was performed to determine significance followed by an all pairwise multiple comparison procedure (Holm-Sidak method). #p < 0.05.
12902_2015_28_MOESM1_ESM.eps
Additional file 2: Figure S2. Detection of cardiac O-GlcNac Protein modifications in MuRF3−/− mice after 26 weeks HFD challenge. A. Densitometric analysis of O-GlcNac/βactin immunoblot (B). N = 3/group. Values expressed as Mean ± SE. A one-way ANOVA was performed to determine significance followed by an All Pairwise Multiple Comparison Procedure (Holm-Sidak method). #p < 0.05.
12902_2015_28_MOESM2_ESM.eps
Additional file 3: Figure S3. mRNA analysis of cardiac PPAR isoform expression in MuRF3 −/− mice. Quantitative RT qPCR analysis of cardiac A. PPARα mRNA, PPARβ mRNA, and PPARγ1 mRNA and B. MuRF1 mRNA and MuRF2 mRNA at baseline and 26 weeks after high fat diet compared to sibling-matched wildtype hearts. N indicated in bars. A one-way ANOVA was performed to determine significance followed by an All Pairwise Multiple Comparison Procedure (Holm-Sidak method). #p < 0.05.
12902_2015_28_MOESM3_ESM.eps
Additional file 4: Figure S4. Enrichment Analysis of Significantly different Metabolits Sets. A. Enrichment by Location-Associated Metabolite Sets B. Pathway Analysis of Metabolite Sets, and C. Disease-Associated Metabolite sets determined from VIP significant and t-test significant metabolites identified. N = 3/group.
12902_2015_28_MOESM4_ESM.pdf
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