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

doi:10.1152/ajpheart.00644.2007

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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 missenseallele for cardiac ${alpha}$ -myosin heavy chain ( ${alpha}$ MHC^R403Q/+ ) developsignificant hypertrophic cardiomyopathy (HCM) compared to wildtypemice ( ${alpha}$ MHC^+/+) after about 30 wks of age. We tested the hypothesisthat myofilament mechanical performance differs between M- ${alpha}$ MHC^R403Q/+and F- ${alpha}$ MHC^R403Q/+ at younger ages (10-20 wks) and could accountfor gender-differences in HCM development. The sensitivity ofchemically-skinned myocardial strips to calcium activation (pCa₅₀)was significantly (P<0.05) enhanced in M mice independentof genotype (M- ${alpha}$ MHC^R403Q/+ 5.70±0.06; M- ${alpha}$ MHC^+/+ 5.63±0.05;F- ${alpha}$ MHC^R403Q/+ 5.57±0.03; F- ${alpha}$ MHC^+/+ 5.54±0.04) by two-wayANOVA, while maximum developed tension (T_max) was significantlyenhanced in ${alpha}$ MHC^R403Q/+ independent of gender (M- ${alpha}$ MHC^R403Q/+ 29.3±2.3;M- ${alpha}$ MHC^+/+ 26.0±1.4; F- ${alpha}$ MHC^R403Q/+ 30.2±2.1; F- ${alpha}$ MHC^+/+26.2±1.2 mN.mm^-2). The frequency of maximum work generatedby sinusoidal length perturbation was significantly higher in ${alpha}$ MHC^R403Q/+ compared to gender-matched controls (M- ${alpha}$ MHC^R403Q/+2.26±0.47; M- ${alpha}$ MHC^+/+ 1.29±0.18; F- ${alpha}$ MHC^R403Q/+ 3.21±0.33;F- ${alpha}$ MHC^+/+ 2.52±0.36 Hz). Unloaded shortening velocity (V_slack)was significantly enhanced in ${alpha}$ MHC^R403Q/+ and in F mice (M- ${alpha}$ MHC^R403Q/+2.26±0.47; M- ${alpha}$ MHC^+/+ 1.29±0.18; F- ${alpha}$ MHC^R403Q/+ 3.21±0.33;F- ${alpha}$ MHC^+/+ 2.52±0.36 ML/s), and normalized mechanical power(P_max), calculated from the tension-velocity relationship, wassignificantly enhanced in ${alpha}$ MHC^R403Q/+ independent of gender (M- ${alpha}$ MHC^R403Q/+60±2 10^-3; M- ${alpha}$ MHC^+/+ 37±3 10^-3; F- ${alpha}$ MHC^R403Q/+ 57±310^-3; F- ${alpha}$ MHC^+/+ 25±3 10^-3 ML/s x T/ T_max). We did not finda statistically significant gender x mutation interaction forany measure of myofilament performance. Therefore, sarcomericincorporation of the R403Q myosin similarly enhanced LV myofilamentmechanical performance in both M and F. The gender-dependentdevelopment of HCM due to the R403Q myosin may then be inhibitedby female sex hormones, which may additionally underlie theobserved gender differences for pCa₅₀ and V_slack.

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