MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet

Jun He, Megan T. Quintana, Jenyth Sullivan, Traci Parry, Trisha Grevengoed, Jonathan C. Schisler, Joseph A Hill, Cecelia C. Yates, Rudo F. Mapanga, M. Faadiel Essop, William E. Stansfield, James R. Bain, Christopher B. Newgard, Michael J. Muehlbauer, Yipin Han, Brian A. Clarke, Monte S. Willis

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: In 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 PPARaα, 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. Methods: MuRF2-/- 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 PPARaα, PPARβ, and PPARγ1-regulated mRNA expression. Results: MuRF2 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 PPARaα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2's regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARaα 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. Conclusions: Mutations 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 PPARaα and PPARγ1 activities in vivo via post-translational modification without degradation.

Original languageEnglish (US)
Article number97
JournalCardiovascular Diabetology
Volume14
Issue number1
DOIs
StatePublished - Aug 5 2015

Fingerprint

Diabetic Cardiomyopathies
High Fat Diet
Fingers
Weight Gain
Peroxisome Proliferator-Activated Receptors
Muscles
Transcription Factors
Ubiquitination
Ligases
Ubiquitin
Myocardium
Familial Hypertrophic Cardiomyopathy
Serum Response Factor
Polyubiquitin
Left Ventricular Dysfunction
Post Translational Protein Processing
Glycogen

Keywords

  • Diabetic cardiomyopathy
  • Multi-ubiquitin
  • MuRF2
  • Post-translational modification
  • PPAR
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet. / He, Jun; Quintana, Megan T.; Sullivan, Jenyth; Parry, Traci; Grevengoed, Trisha; Schisler, Jonathan C.; Hill, Joseph A; Yates, Cecelia C.; Mapanga, Rudo F.; Essop, M. Faadiel; Stansfield, William E.; Bain, James R.; Newgard, Christopher B.; Muehlbauer, Michael J.; Han, Yipin; Clarke, Brian A.; Willis, Monte S.

In: Cardiovascular Diabetology, Vol. 14, No. 1, 97, 05.08.2015.

Research output: Contribution to journalArticle

He, J, Quintana, MT, Sullivan, J, Parry, T, Grevengoed, T, Schisler, JC, Hill, JA, Yates, CC, Mapanga, RF, Essop, MF, Stansfield, WE, Bain, JR, Newgard, CB, Muehlbauer, MJ, Han, Y, Clarke, BA & Willis, MS 2015, 'MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet', Cardiovascular Diabetology, vol. 14, no. 1, 97. https://doi.org/10.1186/s12933-015-0252-x
He, Jun ; Quintana, Megan T. ; Sullivan, Jenyth ; Parry, Traci ; Grevengoed, Trisha ; Schisler, Jonathan C. ; Hill, Joseph A ; Yates, Cecelia C. ; Mapanga, Rudo F. ; Essop, M. Faadiel ; Stansfield, William E. ; Bain, James R. ; Newgard, Christopher B. ; Muehlbauer, Michael J. ; Han, Yipin ; Clarke, Brian A. ; Willis, Monte S. / MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet. In: Cardiovascular Diabetology. 2015 ; Vol. 14, No. 1.
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T1 - MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet

AU - He, Jun

AU - Quintana, Megan T.

AU - Sullivan, Jenyth

AU - Parry, Traci

AU - Grevengoed, Trisha

AU - Schisler, Jonathan C.

AU - Hill, Joseph A

AU - Yates, Cecelia C.

AU - Mapanga, Rudo F.

AU - Essop, M. Faadiel

AU - Stansfield, William E.

AU - Bain, James R.

AU - Newgard, Christopher B.

AU - Muehlbauer, Michael J.

AU - Han, Yipin

AU - Clarke, Brian A.

AU - Willis, Monte S.

PY - 2015/8/5

Y1 - 2015/8/5

N2 - Background: In 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 PPARaα, 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. Methods: MuRF2-/- 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 PPARaα, PPARβ, and PPARγ1-regulated mRNA expression. Results: MuRF2 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 PPARaα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2's regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARaα 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. Conclusions: Mutations 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 PPARaα and PPARγ1 activities in vivo via post-translational modification without degradation.

AB - Background: In 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 PPARaα, 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. Methods: MuRF2-/- 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 PPARaα, PPARβ, and PPARγ1-regulated mRNA expression. Results: MuRF2 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 PPARaα- and PPARγ1-regulated gene expression by RT-qPCR, consistent with MuRF2's regulation of these transcription factors in vivo. Mechanistically, MuRF2 mono-ubiquitinated PPARaα 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. Conclusions: Mutations 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 PPARaα and PPARγ1 activities in vivo via post-translational modification without degradation.

KW - Diabetic cardiomyopathy

KW - Multi-ubiquitin

KW - MuRF2

KW - Post-translational modification

KW - PPAR

KW - Ubiquitin ligase

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