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Biological/Clinical Application 2
PI: Anne Murphy Collaborator: Gerald Hart
Myofilament PTMs in diabetic cardiomyopathy
The myofilament subproteome is the dominant subproteome in the myocyte and is responsible for muscle contraction. Diabetic patients have an increased risk of developing systolic and diastolic cardiac dysfunction and HF. Diabetic cardiomyopathy was initially defined in 1972 as cardiac dysfunction in diabetic patients, which is not secondary to hypertension or coronary artery disease. The cellular mechanisms of diabetic cardiomyopathy are only partially understood and it is clear this is a complex phenotype in which oxidative stress may play a role. It is clear that myofilament dysfunction is present in diabetic animal models and in human diabetic cardiomyocytes. The Murphy laboratory has a long time interest in the regulation of myofilament function in health and disease by PTMs including phosphorylation, oxidation, and regulated proteolysis. Notably, in addition to phosphorylation, O-linked modifications of Ser and Thr by β-N-acetyl-D glucosamine (O-GlcNAc) could regulate cardiac muscle function. Thus, we will address the functional impact of GlcNAc modification of the myofilament in diabetes.
Goal 1: To investigate the quantitative changes of O-GlcNAc modification and phosphorylation at both a global level and specific myofilament protein level as a function of diabetes,
Rationale: In our early studies using an older technology for assessing O-GlcNAc, Murphy’s and Hart’s groups working together identified a number of GlcNAcylated proteins in cardiac myofilaments from control rats including, myosin heavy and light chains, actin and cardiac troponin I (cTnI). Exposure to exogenous GlcNAc, raised O-GlcNAc modification in the muscle, and decreased calcium sensitivity (pCa50), suggesting a direct role for GlcNAcylation in cardiac muscle contraction.
Goal 2: To determine the functional consequences of altered PTMs of the myofilament proteins in diabetes and to assess whether decreased O-GlcNAc modification of cardiac proteins improves cardiac function in cardiac muscle in diabetic models or in vitro in myocytes exposed to hyperglycemia.
Rationale: One hypothesis that will be addressed is whether excess modification of myofilament and other cardiac proteins by O-GlcNAc directly contributes to myofilaments and contractile dysfunction in diabetic cardiomyopathy.
Goal 3: To quantify each phosphorylation and O-GlcNAc modified residue of each myofilament protein in tissue obtained from human failing hearts with and without documented diabetes.
Rationale: In order to better understand the alternations in O-GlcNAc and phospho modifications in human diabetic heart disease we will extend these measurements to human myocardial samples.