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

Abstract

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 1 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 (=−log10[Ca2+]) values ranging from 9.0 to 4.5. The short-range forces elicited by controlled length changes were ~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 β myosin heavy chain. This molecular mechanism can explain the increased short-ranges forces observed in the diabetic tissue if β myosin molecules remain bound between the filaments for longer durations than α molecules during imposed movements. These results suggest that interventions that decrease myosin attachment times may be useful treatments for diastolic dysfunction associated with diabetes.

Chronic Rho-kinase inhibition improves left ventricular contractile dysfunction in early type-1 diabetes by increasing myosin cross-bridge extension

“…In our study, MLC-2 phosphorylation did not differ among the groups and the lower MyBP-C phosphorylation in the vehicle-treated diabetic group was not significant. In contrast, Chung and colleagues [ 48 ] found that myocardial MLC-2 phosphorylation was significantly reduced in the early diabetic heart with no change in MyBP-C phosphorylation. However, Korte et al [ 49 ] have reported significant reductions in MyBP-C phosphorylation in the myocardium of diabetic swine.…”

Dynamic coupling of regulated binding sites and cycling myosin heads in striated muscle

“…Specifically, multidimensional minimization was used to fit the predicted force responses to tension-recovery records previously measured using myocardial preparations isolated from diabetic rats. These samples were useful for this analysis because, unlike most myocardial preparations from rodents, they only contained a single isoform of myosin heavy chain—in this case, the slower cycling β type ( Chung et al, 2013 ).…”

“…As a result of this treatment, the myocardial samples contained only the β isoform of myosin heavy chain. Summary data describing the functional properties and the myosin heavy chain content of these preparations have been published ( Chung et al, 2013 ).…”

Protective effects of sodium selenite on lead nitrate-induced hepatotoxicity in diabetic and non-diabetic rats

“…The streptozotosin (STZ) induced diabetes models utilizes the STZ toxin to damage pancreatic ß cells (Chung et al, 2014). It has been shown that under diabetic conditions, increased of lipid peroxidation and alters of antioxidant enzyme activities detected (Schmatz et al, 2012).…”