Abstract
Two novel mutations (G159D and L29Q) in cardiac troponin C (CTnC) associate their phenotypic outcomes with dilated (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Current paradigms propose that sarcomeric mutations associated with DCM decrease the myofilament Ca2+ sensitivity, whereas those associated with HCM increase it. Therefore, we incorporated the mutant CTnCs into skinned cardiac muscle in order to determine if their effects on the Ca2+ sensitivities of tension and ATPase activity coincide with the current paradigms and phenotypic outcomes. The G159D-CTnC decreases the Ca2+ sensitivity of tension and ATPase activation and reduces the maximal ATPase activity when incorporated into regulated actomyosin filaments. Under the same conditions, the L29Q-CTnC has no effect. Surprisingly, changes in the apparent G159D-CTnC Ca2+ affinity measured by tension in fibers do not occur in the isolated CTnC, and large changes measured in the isolated L29Q-CTnC do not manifest in the fiber. These counterintuitive findings are justified through a transition in Ca2+ affinity occurring at the level of cardiac troponin and higher, implying that the true effects of these mutations become apparent as the hierarchical level of the myofilament increases. Therefore, the contractile apparatus, representing a large cooperative machine, can provide the potential for a change (G159D) or no change (L29Q) in the Ca2+ regulation of contraction. In accordance with the clinical outcomes and current paradigms, the desensitization of myofilaments from G159D-CTnC is expected to weaken the contractile force of the myocardium, whereas the lack of myofilament changes from L29Q-CTnC may preserve diastolic and systolic function.
Highlights
Two novel mutations (G159D and L29Q) in cardiac troponin C (CTnC) associate their phenotypic outcomes with dilated (DCM) and hypertrophic cardiomyopathy (HCM), respectively
The first cardiac troponin C (CTnC) mutation (E59D/D75Y) was found in an explanted heart from an adult male who died from idiopathic dilated cardiomyopathy (DCM) [18]; the second mutation (L29Q) was found in a living 60-year-old male diagnosed with HCM, despite having preserved diastolic and systolic function [19]; and the third (G159D) was found by linkage analysis and cosegregation studies in more than three affected families with DCM [20, 21]
Summary of pCa-tension relationships of skinned cardiac fibers reconstituted with mutant CTnCs
Summary
Two novel mutations (G159D and L29Q) in cardiac troponin C (CTnC) associate their phenotypic outcomes with dilated (DCM) and hypertrophic cardiomyopathy (HCM), respectively. As the number of in vitro-characterized mutations continues to grow, a developing paradigm emerges that associates decreases in the myofilament Ca2ϩ sensitivity with DCM [3,4,5,6,7] and associates increases with HCM (4, 6 –12) and restrictive cardiomyopathy [13,14,15,16,17]. This suggests that distinct effects on the Ca2ϩ-dependent processes of the myofilament are critical determinants of the severity and molecular pathologies of these diseases. With the decline of Ca2ϩ during diastole, Ca2ϩ dissociates from CTnC, and the inhibitory actions of CTnI and Tm are restored
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