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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1939    most recent 00644.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Palmer, B. M. Articles by Maughan, D. W. PubMed PubMed Citation Articles by Palmer, B. M. Articles by Maughan, D. W.

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

¹Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont; and ²Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, Boston, Massachusetts

Submitted 5 June 2007 ; accepted in final form 11 February 2008

Male but not female mice carrying a single R403Q missense allele for cardiac -myosin heavy chain (M-MHC^R403Q/+ and F-MHC^R403Q/+, respectively) develop significant hypertrophic cardiomyopathy (HCM) compared with male and female wild-type mice (M-MHC^+/+ and F-MHC^+/+, respectively) after 30 wk of age. We tested the hypothesis that myofilament mechanical performance differs between M-MHC^R403Q/+ and F-MHC^R403Q/+ 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 (pCa₅₀) was significantly (P < 0.05) enhanced in male mice independent of genotype (M-MHC^R403Q/+: 5.70 ± 0.06, M-MHC^+/+: 5.63 ± 0.05, F-MHC^R403Q/+: 5.57 ± 0.03, F-MHC^+/+: 5.54 ± 0.04) by two-way ANOVA, whereas maximum developed tension was significantly enhanced in -MHC^R403Q/+ independent of sex (M-MHC^R403Q/+: 29.3 ± 2.3, M-MHC^+/+: 26.0 ± 1.4, F-MHC^R403Q/+: 30.2 ± 2.1, F-MHC^+/+: 26.2 ± 1.2 mN/mm²). The frequency of maximum work generated by sinusoidal length perturbation was significantly higher in MHC^R403Q/+ mice than in sex-matched controls (M-MHC^R403Q/+: 2.26 ± 0.47, M-MHC^+/+: 1.29 ± 0.18, F-MHC^R403Q/+: 3.21 ± 0.33, F-MHC^+/+: 2.52 ± 0.36 Hz). Unloaded shortening velocity was significantly enhanced in MHC^R403Q/+ and in female mice (M-MHC^R403Q/+: 2.26 ± 0.47, M-MHC^+/+: 1.29 ± 0.18, F-MHC^R403Q/+: 3.21 ± 0.33, F-MHC^+/+: 2.52 ± 0.36 muscle lengths/s), and normalized mechanical power, calculated from the tension-velocity relationship, was significantly enhanced in MHC^R403Q/+ independent of sex (M-MHC^R403Q/+: 60 ± 2 10^–3, M-MHC^+/+: 37 ± 3 10^–3, F-MHC^R403Q/+: 57 ± 3 10^–3, F-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 pCa₅₀ and unloaded shortening velocity.

hypertrophic cardiomyopathy; myosin heavy chain; isometric tension; calcium sensitivity; force-velocity