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(Circulation Research. 2008;103:1354.)
© 2008 American Heart Association, Inc.

Reports

O-Linked GlcNAc Modification of Cardiac Myofilament Proteins

A Novel Regulator of Myocardial Contractile Function

Genaro A. Ramirez-Correa^*, Wenhai Jin^*, Zihao Wang^*, Xin Zhong, Wei Dong Gao, Wagner B. Dias, Cecilia Vecoli, Gerald W. Hart, Anne M. Murphy

From the Departments of Pediatrics (G.A.R.-C., W.J., A.M.M.) and Medicine (C.V.), Division of Cardiology; Departments of Biological Chemistry (Z.W., W.B.D., G.W.H.) and Anesthesia and Critical Care Medicine (X.Z., W.D.G.), Johns Hopkins University School of Medicine, Baltimore, Md; and Department of Pathophysiology (X.Z.), Harbin Medical University, People’s Republic of China.

Correspondence to Anne M. Murphy, 720 Rutland Ave, Ross Bldg 1144, Baltimore, MD 21205. E-mail murphy{at}jhmi.edu

Abstract

In addition to O-phosphorylation, O-linked modifications of serine and threonine by β-N-acetyl-D-glucosamine (GlcNAc) may regulate muscle contractile function. This study assessed the potential role of O-GlcNAcylation in cardiac muscle contractile activation. To identify specific sites of O-GlcNAcylation in cardiac myofilament proteins, a recently developed methodology based on GalNAz-biotin labeling followed by dithiothreitol replacement and light chromatography/tandem mass spectrometry site mapping was adopted. Thirty-two O-GlcNAcylated peptides from cardiac myofilaments were identified on cardiac myosin heavy chain, actin, myosin light chains, and troponin I. To assess the potential physiological role of the GlcNAc, force–[Ca²⁺] relationships were studied in skinned rat trabeculae. Exposure to GlcNAc significantly decreased calcium sensitivity (pCa50), whereas maximal force (F_max) and Hill coefficient (n) were not modified. Using a pan-specific O-GlcNAc antibody, it was determined that acute exposure of myofilaments to GlcNAc induced a significant increase in actin O-GlcNAcylation. This study provides the first identification of O-GlcNAcylation sites in cardiac myofilament proteins and demonstrates their potential role in regulating myocardial contractile function.

Key Words: O-GlcNAc • myofilaments • posttranslational modifications • cardiac contractility • diabetic cardiomyopathy

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