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

AUTHORS: 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 Cole, Luigi Marchionni, Nazareno Paolocci, Gerald W. Hart and Anne M. Murphy

JOURNAL: Diabetes. 2015 Jun 24. pii: db141107. [Epub ahead of print]


Contractile dysfunction and increased deposition of O-GlcNAcylation in cardiac proteins are a hallmark of the diabetic heart. However, whether and how this post-translational alteration contributes to lower cardiac function remains unclear. Using a refined β-elimination/Michael addition with Tandem Mass Tags (TMT) labeling proteomic technique, here we show that CpOGA, a bacterial analogue of O-GlcNAcase (OGA) that cleaves O-GlcNAc in vivo, removes site-specific O-GlcNAcylation from myofilaments, restoring Ca2+ sensitivity in 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 chain1, 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 activities rather than to changes in their overall extent. Thus, preventing sarcomeric OGT and OGA displacement represents a new possible strategy for treating diabetic cardiomyopathy.

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