The Impact of Biological Sex on Crossbridge Cycling Kinetics in Mice Expressing the R403Q Mutation

Congestive heart failure represents one of the leading causes of death in industrialized countries. A subset of heart failure situations are linked to genetic mutations, many of which reside in sarcomeric proteins. With the prevalence of mutations as approximately 1:500, the location of a mutation plays a direct role in the severity and lethality of the resulting disease state. The point mutation Arg403Glu (R403Q) located on the myosin heavy chain molecule is no exception with a resulting development of left ventricular hypertrophy, myocyte disarray, and increased cellular fibrosis. Given the severity of this mutation in humans, a mouse model was developed to recapitulate these phenotypic characteristics. An additional confounding factor often overlooked when studying the effects of cardiac disease is the role of biological sex. We, therefore, tested the hypothesis that R403Q mice will display altered crossbridge kinetics, specifically an increase in functioning at the expense of energy efficiency, and that biological sex will impact the cardiac response to the R403Q mutation in terms of both crossbridge functioning and post-translational modifications. To do this, we used both male and female R403Q transgenic mice and quantified myofilament mechanical properties including Ca²⁺ sensitivity, crossbridge cycling kinetics, and tension cost of contraction. In addition, phosphorylation patterning was quantified for one of the central, sarcomeric regulatory proteins, cardiac troponin I. We used 2 month animals which do not display overt pathology in the form of hypertrophy in order to minimize downstream, confounding effects. We were able to find that disease and biological sex played an important role in defining these parameters and suggests females are able to better compensate to the presence of altered sarcomeric interactions. Future investigations should focus on altered kinase activity, possibly driven by interactions with estrogen, in order to better define how females can retain cardiac functioning given a disease condition