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Two DCM mutants (E40K and E54K) of tropomyosin (Tm) were examined using the thin-filament extraction/reconstitu­tion technique. The effects of the Ca 2+ , ATP, phos­phate (Pi), and ADP concentrations on isometric tension and its transients were studied at 25°C, and the results were com­pared to those for the WT protein. Our results indicate that both E40K and E54K have a significantly lower  T   HC  (high Ca 2+  ten­sion at pCa 4.66) (E40K: 1.21±0.06  T   a , ±SEM, N = 34; E54K: 1.24±0.07  T   a , N = 28), a significantly lower  T   LC  (low- Ca 2+  tension at pCa 7.0) (E40K: 0.07±0.02  T   a , N = 34; E54K: 0.06±0.02  T   a , N = 28), and a significantly lower  T   act  (Ca 2+  activatable tension) ( T   act  =  T   HC –T LC,  E40K: 1.15±0.08  T   a , N = 34; E54K: 1.18±0.06  T   a , N = 28) than WT ( T   HC  = 1.53±0.07  T   a ,  T   LC  = 0.12±0.01  T   a ,  T   act  = 1.40±0.07  T   a , N = 25). All tensions were normalized to  T   a  ( = 13.9±0.8 kPa, N = 57), the ten­sion of actin-filament reconstituted cardiac fibers (myocardium) under the standard activating conditions. The Ca 2+  sensitivity (pCa 50 ) of E40K (5.23±0.02, N = 34) and E54K (5.24±0.03, N = 28) was similar to that of the WT protein (5.26±0.03, N = 25). The cooper­a­tivity increased significantly in E54K (3.73±0.25, N = 28) compared to WT (2.80±0.17, N = 25). Seven kinetic constants were deduced using sinusoidal analysis at pCa 4.66. These results enabled us to calculate the cross-bridge distribution in the strongly attached states, and thereby deduce the force/cross-bridge. The results indicate that the force/cross-bridge is ∼15% less in E54K than WT, but remains similar to that of the WT protein in the case of E40K. We conclude that over-inhibition of the actomyosin interaction by E40K and E54K Tm mutants leads to a decreased force-generating ability at systole, which is the main mechanism underlying the early pathogenesis of DCM.

DCM-Related Tropomyosin Mutants E40K/E54K Over-Inhibit the Actomyosin Interaction and Lead to a Decrease in the Number of Cycling Cross-Bridges