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Diabetes. 2015 Oct;64(10):3573-87. doi: 10.2337/db14-1107. Epub 2015 Jun 24.

Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle.

Author information

1
Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD gramirez@jhmi.edu.
2
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD.
3
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS.
4
Division of Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD.
5
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
6
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
7
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.

Abstract

Contractile dysfunction and increased deposition of O-linked β-N-acetyl-d-glucosamine (O-GlcNAc) in cardiac proteins are a hallmark of the diabetic heart. However, whether and how this posttranslational alteration contributes to lower cardiac function remains unclear. Using a refined β-elimination/Michael addition with tandem mass tags (TMT)-labeling proteomic technique, we show that CpOGA, a bacterial analog of O-GlcNAcase (OGA) that cleaves O-GlcNAc in vivo, removes site-specific O-GlcNAcylation from myofilaments, restoring Ca(2+) sensitivity in streptozotocin (STZ) diabetic cardiac muscles. We report that in control rat hearts, O-GlcNAc and O-GlcNAc transferase (OGT) are mainly localized at the Z-line, whereas OGA is at the A-band. Conversely, in diabetic hearts O-GlcNAc levels are increased and OGT and OGA delocalized. Consistent changes were found in human diabetic hearts. STZ diabetic hearts display increased physical interactions of OGA with α-actin, tropomyosin, and myosin light chain 1, along with reduced OGT and increased OGA activities. Our study is the first to reveal that specific removal of O-GlcNAcylation restores myofilament response to Ca(2+) in diabetic hearts and that altered O-GlcNAcylation is due to the subcellular redistribution of OGT and OGA rather than to changes in their overall activities. Thus, preventing sarcomeric OGT and OGA displacement represents a new possible strategy for treating diabetic cardiomyopathy.

PMID:
26109417
PMCID:
PMC4587639
DOI:
10.2337/db14-1107
[Indexed for MEDLINE]
Free PMC Article

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