Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of sex

Male but not female mice carrying a single R403Q missense allele for cardiac alpha-myosin heavy chain (M-alpha MHCR403Q/+ and F-alpha MHCR403Q/+, respectively) develop significant hypertrophic cardiomyopathy (HCM) compared with male and female wild-type mice (M-alpha MHC+/+ and F-alpha MHC+/+, respectively) after similar to 30 wk of age. We tested the hypothesis that myofilament mechanical performance differs between M-alpha MHCR403Q/+ and F-alpha MHCR403Q/+ at younger ages (10-20 wk) and could account for sex differences in HCM development. The sensitivity of chemically skinned myocardial strips to Ca2+ activation (pCa(50)) was significantly (P < 0.05) enhanced in male mice independent of genotype (M-alpha MHCR403Q/+: 5.70 +/- 0.06, M-alpha MHC+/+: 5.63 +/- 0.05, F-alpha MHCR403Q/+: 5.57 +/- 0.03, F-alpha MHC+/+: 5.54 +/- 0.04) by two-way ANOVA, whereas maximum developed tension was significantly enhanced in alpha-MHCR403Q/+ independent of sex (M-alpha MHCR403Q/+: 29.3 +/- 2.3, M-alpha MHC+/+: 26.0 +/- 1.4, F-alpha MHCR403Q/+: 30.2 +/- 2.1, F-alpha MHC+/+: 26.2 +/- 1.2 mN/mm(2)). The frequency of maximum work generated by sinusoidal length perturbation was significantly higher in alpha MHCR403Q/+ mice than in sex-matched controls (M-alpha MHCR403Q/+: 2.26 +/- 0.47, M-alpha MHC+/+: 1.29 +/- 0.18, F-alpha MHCR403Q/+: 3.21 +/- 0.33, F-alpha MHC+/+: 2.52 +/- 0.36 Hz). Unloaded shortening velocity was significantly enhanced in alpha MHCR403Q/+ and in female mice (M-alpha MHCR403Q/+: 2.26 +/- 0.47, M-alpha MHC+/+: 1.29 +/- 0.18, F-alpha MHCR403Q/+: 3.21 +/- 0.33, F-alpha MHC+/+: 2.52 +/- 0.36 muscle lengths/s), and normalized mechanical power, calculated from the tension-velocity relationship, was significantly enhanced in alpha MHCR403Q/+ independent of sex (M-alpha MHCR403Q/+: 60 +/- 2 10(-3), M-alpha MHC+/+: 37 +/- 3 10(-3), F-alpha MHCR403Q/+: 57 +/- 3 10(-3), F-alpha MHC+/+ 25 +/- 3 10(-3) muscle lengths/s x normalized tension). We did not find a statistically significant sex x mutation interaction for any measure of myofilament performance. Therefore, sarcomeric incorporation of the R403Q myosin similarly enhanced left ventricular myofilament mechanical performance in both male and female mice. The sex-dependent development of HCM due to the R403Q myosin may then be inhibited by female sex hormones, which may additionally underlie the observed sex differences for pCa(50) and unloaded shortening velocity.