Changes in crossbridge mechanical properties in diabetic rat cardiomyopathy

Abstract

Diabetes mellitus is associated with an increased risk of heart failure, resulting from a specific cardiomyopathy independent of coronary atherosclerosis. It is not yet established whether altered myocardial function is related to changes in molecular mechanics of myosin. Accordingly, we investigated the total number, single force and kinetics of myosin crossbridges (CB) in a rat model of streptozotocin-induced diabetic cardiomyopathy. Experiments were conducted on left ventricular papillary muscles from male diabetic (D) Wistar (n = 16) and age-matched control (C) rats (n = 15). Mechanical indices including the maximum unloaded shortening velocity V(max) and the maximum total isometric tension normalized per cross-sectional area TF(max) were determined. Using A. F. Huxley's equations, we calculated the total cycling CB number per mm(2) Psi, the elementary force per single CB Pi, the maximum values of the rate constant for CB attachment f(1) and detachment g(1) and g(2), and the turnover rate of myosin ATPase per site k(cat). The D rats exhibited a 25% decrease in TF(max) and a 34% decrease in V(max) as compared to C. This contractile dysfunction was associated with a significant reduction in Psi (9.0 +/- 1.6 in D versus 11.4 +/- 1.9 10(9)mm(-2) in C, P < 0.001) without significant change in Pi (6.1 +/- 0.8 in D versus 6.3 +/- 0.9 pN in C, NS). In the 2 groups, TF(max) correlated positively with Psi (r = 0.76, P < 0.001 and r = 0.64, P < 0.01, in D and C respectively) but no relationship was found between TF(max) and Pi. As compared to C, D showed lower values of f(1), g(1) and g(2), and a slower turnover rate of myosin ATPase. Thus, present data suggested that the cardiac contractile impairment observed in streptozotocin-induced diabetic rat cardiomyopathy was mainly related to a decrease in active CB total number and CB kinetics alterations without significant change in CB single force.