Submitted on June 5, 2007
Accepted on February 11, 2008
Myofilament mechanical performance is enhanced by R403Q myosin in mouse myocardium independent of gender
Bradley M Palmer1*, Yuan Wang2, Polakit Teekakirikul3, J Travis Hinson3, Daine Fatkin4, Stacey Strouse2, Peter VanBuren5, Christine E Seidman6, Jonathan G Seidman6, and David. W. Maughan7
1 Molecular Physiology, University of Vermont, Burlington, Vermont, United States
2 Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, United States
3 Dept. of Genetics, Harvard Medical School, Cambridge, Massachusetts, United States
4 Sr Bernice Research Programme in Inherited Heart Diseases, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
5 Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, United States
6 Harvard Medical School, Dept. of Genetics, Boston, Massachusetts, United States
7 Physiology and Biophysics, University of Vermont, Burlington, United States
* To whom correspondence should be addressed. E-mail: palmer{at}physiology.med.uvm.edu.
Male (M) but not female (F) mice carrying a single R403Q missense allele for cardiac 
-myosin heavy chain (MHCR403Q/+ ) develop significant hypertrophic cardiomyopathy (HCM) compared to wildtype mice (MHC+/+) after about 30 wks of age. We tested the hypothesis that myofilament mechanical performance differs between M-MHCR403Q/+ and F-MHCR403Q/+ at younger ages (10-20 wks) and could account for gender-differences in HCM development. The sensitivity of chemically-skinned myocardial strips to calcium activation (pCa50) was significantly (P<0.05) enhanced in M mice independent of genotype (M-MHCR403Q/+ 5.70±0.06; M-MHC+/+ 5.63±0.05; F-MHCR403Q/+ 5.57±0.03; F-MHC+/+ 5.54±0.04) by two-way ANOVA, while maximum developed tension (Tmax) was significantly enhanced in MHCR403Q/+ independent of gender (M-MHCR403Q/+ 29.3±2.3; M-MHC+/+ 26.0±1.4; F-MHCR403Q/+ 30.2±2.1; F-MHC+/+ 26.2±1.2 mN.mm-2). The frequency of maximum work generated by sinusoidal length perturbation was significantly higher in MHCR403Q/+ compared to gender-matched controls (M-MHCR403Q/+ 2.26±0.47; M-MHC+/+ 1.29±0.18; F-MHCR403Q/+ 3.21±0.33; F-MHC+/+ 2.52±0.36 Hz). Unloaded shortening velocity (Vslack) was significantly enhanced in MHCR403Q/+ and in F mice (M-MHCR403Q/+ 2.26±0.47; M-MHC+/+ 1.29±0.18; F-MHCR403Q/+ 3.21±0.33; F-MHC+/+ 2.52±0.36 ML/s), and normalized mechanical power (Pmax), calculated from the tension-velocity relationship, was significantly enhanced in MHCR403Q/+ independent of gender (M-MHCR403Q/+ 60±2 10-3; M-MHC+/+ 37±3 10-3; F-MHCR403Q/+ 57±3 10-3; F-MHC+/+ 25±3 10-3 ML/s x T/ Tmax). We did not find a statistically significant gender x mutation interaction for any measure of myofilament performance. Therefore, sarcomeric incorporation of the R403Q myosin similarly enhanced LV myofilament mechanical performance in both M and F. The gender-dependent development of HCM due to the R403Q myosin may then be inhibited by female sex hormones, which may additionally underlie the observed gender differences for pCa50 and Vslack.
