Mechanical defects of muscle fibers with myosin light chain mutants that cause cardiomyopathy.

Familial hypertrophic cardiomyopathy is a disease caused by single mutations in several sarcomeric proteins, including the human myosin ventricular regulatory light chain (vRLC). The effects of four of these mutations (A13T, F18L, E22K, and P95A) in vRLC on force generation were determined as a function of Ca(2+) concentration. The endogenous RLC was removed from skinned rabbit psoas muscle fibers, and replaced with either rat wildtype vRLC or recombinant rat vRLC (G13T, F18L, E22K, and P95A). Compared to fibers with wildtype rat vRLC, the E22K mutant increased Ca sensitivity of force generation, whereas the G13T and F18L mutants decreased the Ca sensitivity, and the P95A mutant had no significant effect. None of the RLC mutants affected the maximal tension (observed at saturating Ca(2+) concentrations), except for F18L, which decreased the maximal tension to 69 +/- 10% of the wildtype value. Of the mutant RLCs, only F18L decreased the cooperativity of activation of force generation. These results suggest that the primary cause of familial hypertrophic cardiomyopathy, in some cases, is perturbation in the Ca sensitivity of force generation, in which Ca-sensitizing or Ca-desensitizing effects can lead to similar disease phenotypes.