Desensitization of Myofilaments to Ca ²⁺ as a Therapeutic Target for Hypertrophic Cardiomyopathy With Mutations in Thin Filament Proteins

Abstract

Background Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca2+ sensitivity and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype. Methods and Results We used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca2+ sensitivity, severe hypertrophy and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca2+ sensitivity in Tm180 mice by generating a double transgenic (DTG) mouse line. We crossed Tm180 mice with mice expressing a pseudo-phosphorylated cardiac troponin I (cTnI) (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca2+ sensitivity compared to wild-type mice. The development of pathological hypertrophy did not occur in mice expressing both Tm180 and TnI-PP. Left ventricle performance was improved in DTG compared to their Tm180 littermates, which express wild-type cTnI. Hearts of DTG mice demonstrated no changes in expression of phospholamban (PLN) and Serca2a, increased levels of PLN and TnT phosphorylation, and reduced phosphorylation of TnI compared to Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of ERK1/2 and GATA-4 in Tm180 hearts. Conclusions Our data strongly indicate that reduction of myofilament sensitivity to Ca2+ and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.

Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility

“…Based on the current computational models, we and others have designed engineered cTnC variants with altered Ca 2+ binding affinities (to cTn) and demonstrated that those variants alter the contractile function in cardiomyocytes and correct or prevent disease-related aberrant Ca 2+ binding and contractile function [163, 187, 188, 203-209]. These studies also provide important implications with respect to the design of Ca 2+ sensitizing or desensitizing small molecules or drugs.…”

Amino Acid Changes at Arginine 204 of Troponin I Result in Increased Calcium Sensitivity of Force Development

“…These results suggest that the R204 residue is important in cTnI function and that increased Ca 2+ sensitivity may be a major factor in HCM. The increase in myofilament sensitivity to Ca 2+ is important since reduction in the Ca 2+ sensitivity was found to prevent the development of HCM (Alves et al, 2014). Others have suggested that increased Ca 2+ -sensitivity is associated with HCM (Wei and Jin, 2015).…”

The genetic basis of hypertrophic cardiomyopathy in cats and humans

“…77 In support of this idea, normalization of Ca 2+ sensitivity of tension in a mouse model of HCM prevented the development of HCM in one study. 78 The authors concluded that myofilament desensitization to Ca 2+ could be a therapeutic target for treatment of HCM. While this approach could be widely applicable in principle, it is still likely to be a vast oversimplification considering the heterogeneity that underlies HCM.…”