title: Contractile apparatus dysfunction early in the pathophysiology of diabetic cardiomyopathy.
abstract: Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure in patients. Independent of hypertension and coronary artery disease, diabetes is associated with a specific cardiomyopathy, known as diabetic cardiomyopathy (DCM). Four decades of research in experimental animal models and advances in clinical imaging techniques suggest that DCM is a progressive disease, beginning early after the onset of type 1 and type 2 diabetes, ahead of left ventricular remodeling and overt diastolic dysfunction. Although the molecular pathogenesis of early DCM still remains largely unclear, activation of protein kinase C appears to be central in driving the oxidative stress dependent and independent pathways in the development of contractile dysfunction. Multiple subcellular alterations to the cardiomyocyte are now being highlighted as critical events in the early changes to the rate of force development, relaxation and stability under pathophysiological stresses. These changes include perturbed calcium handling, suppressed activity of aerobic energy producing enzymes, altered transcriptional and posttranslational modification of membrane and sarcomeric cytoskeletal proteins, reduced actin-myosin cross-bridge cycling and dynamics, and changed myofilament calcium sensitivity. In this review, we will present and discuss novel aspects of the molecular pathogenesis of early DCM, with a special focus on the sarcomeric contractile apparatus.
authors.affiliation: Mark T Waddingham, Amanda J Edgley, Darren J Kelly, Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3065, Australia.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Waddingham
authors.affiliation: Mark T Waddingham, Amanda J Edgley, Darren J Kelly, Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3065, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Edgley
authors.affiliation: Mark T Waddingham, Amanda J Edgley, Darren J Kelly, Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3065, Australia.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tsuchimochi
authors.affiliation: Mark T Waddingham, Amanda J Edgley, Darren J Kelly, Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3065, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.affiliation: Mark T Waddingham, Amanda J Edgley, Darren J Kelly, Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3065, Australia.
authors.forename: Mikiyasu
authors.initials: M
authors.lastname: Shirai
authors.affiliation: Mark T Waddingham, Amanda J Edgley, Darren J Kelly, Department of Medicine, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria 3065, Australia.
authors.forename: James T
authors.initials: JT
authors.lastname: Pearson
keywords: Diabetes; Insulin resistance; Myocardium; Prediabetes; Protein kinase C; Rho kinase; Sarcomere