The R403Q mutation alters isometric and energetic properties in 2 month mice (1081.1)

Abstract

Familial hypertrophic cardiomyopathy is a primary disease of the sarcomere. The R403Q mutation resides at the actin‐interaction site on myosin and leads to progressive hypertrophic cardiomyopathy that can lead to sudden cardiac death or congestive heart failure. We hypothesized that the R403Q mutation intrinsically increases the energetic cost of contraction.To do this, we assessed Ca2+‐sensitivity of tension and cross‐bridge kinetics in de‐membranated cardiac trabeculae from wild‐type (WT) and R403Q hearts at 2 months of age. We measured cross‐bridge kinetics using 2 methods: (1) the rate of ATP hydrolysis (off‐rate) by NADH oxidation, and (2) the rate of force redevelopment (ktr) by a rapid release‐restretch protocol.Male R403Q mice display a decrease in Ca2+ sensitivity compared to WT males and females at SL 2.0μm. R403Q males display increased tension cost at SL 2.0μm when compared to WT counterparts. At maximal activation, the rate of force redevelopment is not significantly different between R403Q and WT males. Myosin heavy chain isoform gel analysis reveals no difference in β‐myosin content between R403Q mice and WT controls.Although maximal ktr is not significantly different between WT and R403Q males, an increase in ATP hydrolysis suggests an alteration in binding kinetics. Along with no overt pathology at 2 months, the R403Q mutation alters the energetic cost of contraction and isometric properties.Grant Funding Source: Supported by R01 HL098256A and T32HL007955