Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 535, Issue 1, Pages 39-48Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2012.12.023
Keywords
Hypertrophic cardiomyopathy; SR Ca2+ ATPase (2a) (SERCA2a); cTnI; Site-specific phosphorylation; Phosphate-affinity SDS-PAGE
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Funding
- NIH [HL 098256, HL50560, K02 HL105799]
- National and Mentored Research Science Development Award [K01 AR052840]
- Interdisciplinary Training Grant in Cardiovascular Sciences [HL007249]
- Sarver Heart Center at the University of Arizona
- Steven M. Gootter Foundation
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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 Ca2+-sensitive tension development was due to changes in Ca2+ handling and sarcomeric proteins, including expression of SR Ca2+ ATPase (2a) (SERCA2a), beta-myosin heavy chain (beta-MyHC) and post-translational modifications of myofilament proteins. Female HCM hearts showed an elevation of SERCA2a and beta-MyHC protein whereas male HCM hearts showed a similar elevation of beta-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. (C) 2013 Elsevier Inc. All rights reserved.
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