Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response

Abstract

HCM phenotype was not associated with differences in myofilament Ca 2+ sensitivity between TG/PLN and TG/PLNKO mice. Moreover, compared to standard systolic echo parameters, such as ejection fraction (EF), speckle strain measurements provided a more sensitive approach to detect early systolic dysfunction in TG/PLN mice. In summary, our results indicate that targeting diastolic dysfunction through altering Ca 2+ fluxes with no change in myofilament response to Ca 2+ was able to prevent the development of the HCM phenotype and should be considered as a potential additional treatment for HCM patients.

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

“…While we recognize that changes in transcript expression do not always correlate with protein function, our data demonstrate that altered mechanics at the molecular level can drive changes in gene expression, showing a mechanobiological link between these processes in HCM. It is worth noting that some of the differentially expressed calcium-handling genes observed here in human cells are different from observations in the R92Q mouse model, which may be due to species differences ( Coppini et al, 2017 ; Chowdhury et al, 2020 ). Interestingly, in mice, ablation of PLN can rescue the HCM phenotype, and it will be interesting to see whether similar results are observed in human cells ( Chowdhury et al, 2020 ).…”

“…It is worth noting that some of the differentially expressed calcium-handling genes observed here in human cells are different from observations in the R92Q mouse model, which may be due to species differences ( Coppini et al, 2017 ; Chowdhury et al, 2020 ). Interestingly, in mice, ablation of PLN can rescue the HCM phenotype, and it will be interesting to see whether similar results are observed in human cells ( Chowdhury et al, 2020 ).…”

Ion Channel Impairment and Myofilament Ca2+ Sensitization: Two Parallel Mechanisms Underlying Arrhythmogenesis in Hypertrophic Cardiomyopathy

“…PLNKO prevented the development of the HCM phenotype (absence of fibrosis, reduced activation of the hypertrophy-related gene expression program) in R92Q transgenic mice, reducing CaMKII phosphorylation but preserving the increased myofilament Ca 2+ sensitivity of force development. These results suggest that the absence of PLN removed the inhibition of SERCA2, allowing an increased activity of the protease that despite its reduced function due to increased ATP consumption, can still reuptake Ca 2+ into SR, preventing the increased diastolic [Ca 2+ ] and the consequent vicious cycle mainly driven by CaMKII phosphorylation and hyperactivation, finally leading to normal relaxation [103]. The central role of intracellular Ca 2+ impairment in the pathogenesis of HCM was also evidenced by Li and coworkers, who developed a knockout Muscle LIM protein (MLP, CSRP3) human embryonic stem cell (hESC) line using a CRISPR/Cas9 technique.…”

Effects of Sarcomere Activators and Inhibitors Targeting Myosin Cross-Bridges on Ca2+-Activation of Mature and Immature Mouse Cardiac Myofilaments

“…One set of experiments employed male and female adult non-transgenic (NTG) or transgenic (TG) adult mice on an FVB/N background expressing ssTnI (TG-ssTnI) in the cardiac compartment, as previously described (Alves et al, 2017). A second set of experiments employed male and female 7-and 14-day old NTG mice and TG mice (TG-cTnT-R92Q) expressing an HCM-linked TnT mutant generated in C57/B6 strain as previously described (Chowdhury et al, 2020;Tardiff et al, 1999). Since it is wellknown that genetic background may have a notable effect on the HCM phenotype (Michele et al, 2002;Prabhakar et al, 2001;Rowlands et al, 2017), we first rederived and characterized TnT-R92Q mice in FVB/N background to be consistent with TG-ssTnI mice.…”