title: Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet.
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.
authors.affiliation: Department of Surgery, University of North Carolina, Chapel Hill, NC, USA. MQuintan@unch.unc.edu.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Quintana
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA. heju@email.unc.edu.|General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People's Republic of China. heju@email.unc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, NC, USA. sullivj@live.unc.edu.
authors.forename: Jenyth
authors.initials: J
authors.lastname: Sullivan
authors.affiliation: Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA. tgreven@live.unc.edu.
authors.forename: Trisha
authors.initials: T
authors.lastname: Grevengoed
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA. schisler@med.unc.edu.|Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA. schisler@med.unc.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schisler
authors.affiliation: North Carolina State University, Department of Engineering, Raleigh, NC, USA. yipinhan97@gmail.com.
authors.forename: Yipin
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX, USA. joseph.hill@UTsouthwestern.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.affiliation: Department of Health Promotions and Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA, USA. CEY4@pitt.edu.
authors.forename: Cecelia C
authors.initials: CC
authors.lastname: Yates
authors.affiliation: Department of Surgery, University of North Carolina, Chapel Hill, NC, USA. William.Stansfield@uhn.ca.
authors.forename: William E
authors.initials: WE
authors.lastname: Stansfield
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa. rfmapanga@sun.ac.za.
authors.forename: Rudo F
authors.initials: RF
authors.lastname: Mapanga
authors.affiliation: Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, 7600, South Africa. mfessop@sun.ac.za.
authors.forename: M Faadiel
authors.initials: MF
authors.lastname: Essop
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA. michael.muehlbauer@duke.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA. chris.newgard@duke.edu.|Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA. chris.newgard@duke.edu.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA. james.bain@duke.edu.|Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University Medical Center, Durham, NC, USA. james.bain@duke.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Bain
authors.affiliation: Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA. monte_willis@med.unc.edu.|McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA. monte_willis@med.unc.edu.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D058065:Diabetic Cardiomyopathies / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D054143:Heart Failure, Systolic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D009124:Muscle Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; C413644:Rnf30 protein, mouse