Thierry Joseph

Changes in crossbridge mechanical properties in diabetic rat cardiomyopathy

AbstractDiabetes 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 Vmax and the maximum total isometric tension normalized per cross–sectional area TFmax were determined. Using A. F. Huxley’s equations, we calculated the total cycling CB number per mm2 Ψ, the elementary force per single CB Π, the maximum values of the rate constant for CB attachment f1 and detachment g1 and g2, and the turnover rate of myosin ATPase per site kcat. The D rats exhibited a 25% decrease in TFmax and a 34% decrease in Vmax as compared to C. This contractile dysfunction was associated with a significant reduction in Ψ (9.0 ± 1.6 in D versus 11.4 ± 1.9 109mm–2 in C, P < 0.001) without significant change in Π (6.1 ± 0.8 in D versus 6.3 ± 0.9 pN in C, NS). In the 2 groups, TFmax correlated positively with Ψ (r = 0.76, P < 0.001 and r = 0.64, P < 0.01, in D and C respectively) but no relationship was found between TFmax and Π. As compared to C, D showed lower values of f1, g1 and g2, 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.

Species-dependent changes in mechano-energetics of isolated cardiac muscle during hypoxia.

Abstract The present study investigates the mechanical and energic changes induced by hypoxia in isolated cardiac muscles of different species characterized by different myosin isoforms. Classic mechanical parameters of contraction and energetic parameters derived from the tension-velocity relationship were studied in rat and guinea pig left ventricular papillary muscles and in frog ventricular strips before and after 15 min hypoxia (n = 8 in each group) The isomyosin pattern is predominantly V1 with high ATPase activity in rat and V3 with low ATPase activity in guinea pig and frog heart ventricles. At baseline, cardiac mechanical performace was greater in rat than in guinea pig and frog muscle, but the economy of tension generation did not differ significantly between the three species. Hypoxia significantly decreased myocardial mechanical performance in al three groups. Mechanical impairment was more marked in rat than in the other two species and was intermediate in guinea pig. The energetic consequences of hypoxia differed according to species and in a different manner from the mechanical parameters. Hypoxia decreased the economy of tension generation in rat heart, in contrast to no change in guinea pig and frog muscle. These results suggest that in terms of mechano-energetic properties, cardiac muscles with V1 isomyosin were more sensitive to hypoxia than those containing V3 isomyosin.