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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Article number36
JournalBMC Endocrine Disorders
Volume15
Issue number1
DOIs
StatePublished - Dec 12 2015

Fingerprint

Diabetic Cardiomyopathies
Peroxisome Proliferators
High Fat Diet
Fingers
Muscles
Peroxisome Proliferator-Activated Receptors
Ubiquitination
Fats
Activating Transcription Factors
Systolic Heart Failure
Striated Muscle
Post Translational Protein Processing
Ligases
Ubiquitin
Glycogen
Adipocytes
Cardiac Myocytes
Echocardiography
Insulin Resistance
Blood Glucose

Keywords

  • Diabetic cardiomyopathy
  • Multi-ubiquitin
  • MuRF3
  • Post-translational modification
  • PPAR
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

Quintana, M. T., He, J., Sullivan, J., Grevengoed, T., Schisler, J., Han, Y., ... Willis, M. S. (2015). Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet. BMC Endocrine Disorders, 15(1), [36]. https://doi.org/10.1186/s12902-015-0028-z

Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet. / Quintana, Megan T.; He, Jun; Sullivan, Jenyth; Grevengoed, Trisha; Schisler, Jonathan; Han, Yipin; Hill, Joseph A; Yates, Cecelia C.; Stansfield, William E.; Mapanga, Rudo F.; Essop, M. Faadiel; Muehlbauer, Michael J.; Newgard, Christopher B.; Bain, James R.; Willis, Monte S.

In: BMC Endocrine Disorders, Vol. 15, No. 1, 36, 12.12.2015.

Research output: Contribution to journalArticle

Quintana, MT, He, J, Sullivan, J, Grevengoed, T, Schisler, J, Han, Y, Hill, JA, Yates, CC, Stansfield, WE, Mapanga, RF, Essop, MF, Muehlbauer, MJ, Newgard, CB, Bain, JR & Willis, MS 2015, 'Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet', BMC Endocrine Disorders, vol. 15, no. 1, 36. https://doi.org/10.1186/s12902-015-0028-z
Quintana, Megan T. ; He, Jun ; Sullivan, Jenyth ; Grevengoed, Trisha ; Schisler, Jonathan ; Han, Yipin ; Hill, Joseph A ; Yates, Cecelia C. ; Stansfield, William E. ; Mapanga, Rudo F. ; Essop, M. Faadiel ; Muehlbauer, Michael J. ; Newgard, Christopher B. ; Bain, James R. ; Willis, Monte S. / Muscle ring finger-3 protects against diabetic cardiomyopathy induced by a high fat diet. In: BMC Endocrine Disorders. 2015 ; Vol. 15, No. 1.
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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.",
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AU - Quintana, Megan T.

AU - He, Jun

AU - Sullivan, Jenyth

AU - Grevengoed, Trisha

AU - Schisler, Jonathan

AU - Han, Yipin

AU - Hill, Joseph A

AU - Yates, Cecelia C.

AU - Stansfield, William E.

AU - Mapanga, Rudo F.

AU - Essop, M. Faadiel

AU - Muehlbauer, Michael J.

AU - Newgard, Christopher B.

AU - Bain, James R.

AU - Willis, Monte S.

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N2 - 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.

AB - 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.

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