Sexually dimorphic myofilament function and cardiac troponin I phosphospecies distribution in hypertrophic cardiomyopathy mice.
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, 10-12month female HCM (harboring a mutant [R403Q] myosin heavy chain) mice presented with proportionately larger hearts than male HCM mice. Next, we determined Ca(2+)-sensitive tension development in demembranated cardiac trabeculae excised from 10-12month female and male HCM mice. Whereas HCM did not impact Ca(2+)-sensitive tension development in male trabeculae, female HCM trabeculae were more sensitive to Ca(2+) 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 Ca(2+) 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.
Department of Physiology, Sarver Molecular Cardiovascular Research Program, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA.
Laurel A K
LA
McKee
Hao
H
Chen
Jessica A
JA
Regan
Samantha M
SM
Behunin
Jeffery W
JW
Walker
John S
JS
Walker
John P
JP
Konhilas
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009129:Muscle Tonus; D009154:Mutation; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D019210:Troponin I / Q000378:metabolism*; D020107:Troponin T / Q000378:metabolism; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism
C551613:Myh7 protein, mouse; C521958:Mylpf protein, mouse; D018994:Myosin Light Chains; D019210:Troponin I; D020107:Troponin T; D024723:Ventricular Myosins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; C506947:Atp2a2 protein, mouse; D002118:Calcium