Sexually dimorphic myofilament function and cardiac troponin i phosphospecies distribution in hypertrophic cardiomyopathy mice

Laurel A.K. McKee, Hao Chen, Jessica A. Regan, Samantha M. Behunin, Jeffery W. Walker, John S. Walker, John P. Konhilas

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The pathological progression of hypertrophic cardiomyopathy (HCM) is sexually dimorphic such that male HCM mice develop phenotypic indicators of cardiac disease well before female HCM mice. Here, we hypothesized that alterations in myofilament function underlies, in part, this sex dimorphism in HCM disease development. Firstly, 10-12 month female HCM (harboring a mutant [R403Q] myosin heavy chain) mice presented with proportionately larger hearts than male HCM mice. Next, we determined Ca2+-sensitive tension development in demembranated cardiac trabeculae excised from 10-12 month female and male HCM mice. Whereas HCM did not impact Ca2+-sensitive tension development in male trabeculae, female HCM trabeculae were more sensitive to Ca2+ than wild-type (WT) counterparts and both WT and HCM males. We hypothesized that the underlying cause of this sex difference in Ca 2+-sensitive tension development was due to changes in Ca 2+ handling and sarcomeric proteins, including expression of SR Ca2+ ATPase (2a) (SERCA2a), β-myosin heavy chain (β-MyHC) and post-translational modifications of myofilament proteins. Female HCM hearts showed an elevation of SERCA2a and β-MyHC protein whereas male HCM hearts showed a similar elevation of β-MyHC protein but a reduced level of cardiac troponin T (cTnT) phosphorylation. We also measured the distribution of cardiac troponin I (cTnI) phosphospecies using phosphate-affinity SDS-PAGE. The distribution of cTnI phosphospecies depended on sex and HCM. In conclusion, female and male HCM mice display sex dimorphic myofilament function that is accompanied by a sex- and HCM-dependent distribution of sarcomeric proteins and cTnI phosphospecies.

Original languageEnglish (US)
Pages (from-to)39-48
Number of pages10
JournalArchives of Biochemistry and Biophysics
Volume535
Issue number1
DOIs
Publication statusPublished - Jul 1 2013
Externally publishedYes

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Keywords

  • cTnI
  • Hypertrophic cardiomyopathy
  • Phosphate-affinity SDS-PAGE
  • Site-specific phosphorylation
  • SR Ca ATPase (2a) (SERCA2a)

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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