BackgroundIn diabetes mellitus the morbidity and mortality of cardiovascular disease is increased and represents an important independent mechanism by which heart disease is exacerbated. The pathogenesis of diabetic cardiomyopathy involves the enhanced activation of PPAR transcription factors, including PPARα, and to a lesser degree PPARβ and PPARγ1. How these transcription factors are regulated in the heart is largely unknown. Recent studies have described post-translational ubiquitination of PPARs as ways in which PPAR activity is inhibited in cancer. However, specific mechanisms in the heart have not previously been described. Recent studies have implicated the muscle-specific ubiquitin ligase muscle ring finger-2 (MuRF2) in inhibiting the nuclear transcription factor SRF. Initial studies of MuRF2−/− hearts revealed enhanced PPAR activity, leading to the hypothesis that MuRF2 regulates PPAR activity by post-translational ubiquitination.MethodsMuRF2−/− mice were challenged with a 26-week 60% fat diet designed to simulate obesity-mediated insulin resistance and diabetic cardiomyopathy. Mice were followed by conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis of intracellular signaling, heart and skeletal muscle morphometrics, and PPARα, PPARβ, and PPARγ1-regulated mRNA expression.ResultsMuRF2 protein levels increase ~20% during the development of diabetic cardiomyopathy induced by high fat diet. Compared to littermate wildtype hearts, MuRF2−/− hearts exhibit an exaggerated diabetic cardiomyopathy, characterized by an early onset systolic dysfunction, larger left ventricular mass, and higher heart weight. MuRF2−/− hearts had significantly increased PPARα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2’s regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARα and PPARγ1 in vitro, consistent with its non-degradatory role in diabetic cardiomyopathy. However, increasing MuRF2:PPARγ1 (>5:1) beyond physiological levels drove poly-ubiquitin-mediated degradation of PPARγ1 in vitro, indicating large MuRF2 increases may lead to PPAR degradation if found in other disease states.ConclusionsMutations in MuRF2 have been described to contribute to the severity of familial hypertrophic cardiomyopathy. The present study suggests that the lack of MuRF2, as found in these patients, can result in an exaggerated diabetic cardiomyopathy. These studies also identify MuRF2 as the first ubiquitin ligase to regulate cardiac PPARα and PPARγ1 activities in vivo via post-translational modification without degradation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0252-x) contains supplementary material, which is available to authorized users.
BackgroundThe 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.MethodsMuRF3−/− 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.ResultsMuRF3−/− 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12902-015-0028-z) contains supplementary material, which is available to authorized users.
IntroductionWorldwide, an estimated 10%–27% of women are sexually assaulted during their lifetime. Despite the enormity of sexual assault as a public health problem, to our knowledge, no large-scale prospective studies of experiences and recovery over time among women presenting for emergency care after sexual assault have been performed.Methods and analysisWomen ≥18 years of age who present for emergency care within 72 hours of sexual assault to a network of treatment centres across the USA are approached for study participation. Blood DNA and RNA samples and brief questionnaire and medical record data are obtained from women providing initial consent. Full consent is obtained at initial 1 week follow-up to analyse blood sample data and to perform assessments at 1 week, 6 weeks, 6 months and 1 year. These assessments include evaluation of survivor life history, current health and recovery and experiences with treatment providers, law enforcement and the legal system.Ethics and disseminationThis study is approved by the University of North Carolina at Chapel Hill’s Institutional Review Board (IRB) and the IRB of each participating study site. We hope to present the results of this study to the scientific community at conferences and in peer-reviewed journals.
Orthopaedic injuries are the norm in children and adolescents injured in ATV accidents. Although some legislation is in place, the level of compliance is unclear. Legislation requiring helmet use and age limits failed in Oklahoma this year. Perhaps a comprehensive community education program would be the most effective in decreasing ATV morbidity and mortality in children.
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