Removal of abnormal myofilament O-GlcNAcylation restores Ca2+ sensitivity in diabetic cardiac muscle

Genaro A. Ramirez-Correa, Junfeng Ma, Chad Slawson, Quira Zeidan, Nahyr S. Lugo-Fagundo, Mingguo Xu, Xiaoxu Shen, Wei Dong Gao, Viviane Caceres, Khalid Chakir, Lauren DeVine, Robert N. Cole, Luigi Marchionni, Nazareno Paolocci, Gerald W. Hart, Anne M. Murphy

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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 sitespecific O-GlcNAcylation from myofilaments, restoring Ca2+ 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 a-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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)3573-3587
Number of pages15
Issue number10
StatePublished - Oct 2015

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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