Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of β myosin heavy chain

Diastolic dysfunction is a clinically significant problem for patients with diabetes and often reflects increased ventricular stiffness. Attached cross-bridges contribute to myocardial stiffness and produce short-range forces, but it is not yet known whether these forces are altered in diabetes. In this study, we tested the hypothesis that cross-bridge-based short-range forces are increased in the streptozotocin (STZ) induced rat model of type I diabetes. Chemically permeabilized myocardial preparations were obtained from 12 week old rats that had been injected with STZ or vehicle 4 weeks earlier, and activated in solutions with pCa (=-log(10)[Ca2+) values ranging from 9.0 to 4.5. The short-range forces elicited by controlled length changes were similar to 67% greater in the samples from the diabetic rats than in the control preparations. This change was mostly due to an increased elastic limit (the length change at the peak short-range force) as opposed to increased passive muscle stiffness. The STZ-induced increase in short-ranges forces is thus unlikely to reflect changes to titin and/or collagen filaments. Gel electrophoresis showed that STZ increased the relative expression of beta myosin heavy chain. This molecular mechanism can explain the increased short-ranges forces observed in the diabetic tissue if beta myosin molecules remain bound between the filaments for longer durations than alpha molecules during imposed movements. These results suggest that interventions that decrease myosin attachment times may be useful treatments for diastolic dysfunction associated with diabetes. (C) 2013 Elsevier Inc. All rights reserved.