Differential Effects of CaMKII Activity in HCM-Linked TNT Mutations

Abstract

Mutations in human cardiac troponin T (hcTnT) account for approximately 5-10% of all Hypertrophic Cardiomyopathy (HCM). Residue 92 (Arg) in cTnT is a mutational hotspot. Despite differing by only a single amino acid, Arg92Leu (R92L) and Arg92Trp (R92W) are associated with varying clinical presentations. In the course of studying the differential effects of the R92 mutations on Ca2+ homeostasis, an increase in phospholamban (PLB) phosphorylation at Thr17 was observed only in R92W mice, suggesting a potential mutation-specific role for CaMKII activation in cTnT-linked HCM. To directly test this hypothesis we crossed CaMKII peptide inhibitor mice (AC3I) to both R92W and R92L transgenic mice to evaluate whether a partial inhibition of CaMKII activity could specifically alter the natural history of HCM via modulation of SERCA2 activity. In the AC3IxR92W mice, a compensatory increase in PKA-mediated PLB-Ser16 phosphorylation led to an increase SERCA2 activity coupled with a decrease in atrial mass, indicating improved cardiac function. AC3IxR92L mice did not show any change in SERCA2 activity or morphology, suggesting minimal role of CaMKII in the progression of R92L-linked HCM. R92W has been shown to cause an increase in the Ca2+ dissociation rate from the thin filament, leading to an increase in resting Ca2+ concentration. This increase in Ca2+ initiates aberrant and likely pathophysiologic CaMKII activity, contributing to the progression of HCM in these patients. Thus, targeting the activity of CaMKII may be a potential drug therapy for patients expressing the R92W mutation. Ongoing work aims to elucidate the effects of conventional drug therapies on mice expressing these two mutations to differentiate treatment for patients.