Sexual dimorphic response to exercise in hypertrophic cardiomyopathy-associated MYBPC3-targeted knock-in mice

Abstract

Hypertrophic cardiomyopathy (HCM), the most common genetic cardiac disorder, is frequently caused by mutations in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Moreover, HCM is the leading cause of sudden cardiac death (SCD) in young athletes. Interestingly, SCD is more likely to occur in male than in female athletes. However, the pathophysiological mechanisms leading to sex-specific differences are poorly understood. Therefore, we studied the effect of sex and exercise on functional properties of the heart and sarcomeres in mice carrying a MYBPC3 point mutation (G > A transition in exon 6) associated with human HCM. Echocardiography followed by isometric force measurements in left ventricular (LV) membrane-permeabilized cardiomyocytes was performed in wild-type (WT) and heterozygous (HET) knock-in mice of both sex (N = 5 per group) in sedentary mice and mice that underwent an 8-week voluntary wheel-running exercise protocol. Isometric force measurements in single cardiomyocytes revealed a lower maximal force generation (F max) of the sarcomeres in male sedentary HET (13.0 ± 1.1 kN/m(2)) compared to corresponding WT (18.4 ± 1.8 kN/m(2)) male mice. Exercise induced a higher F max in HET male mice, while it did not affect HET females. Interestingly, a low cardiac troponin I bisphosphorylation, increased myofilament Ca(2+)-sensitivity, and LV hypertrophy were particularly observed in exercised HET females. In conclusion, in sedentary animals, contractile differences are seen between male and female HET mice. Male and female HET hearts adapted differently to a voluntary exercise protocol, indicating that physiological stimuli elicit a sexually dimorphic cardiac response in heterozygous MYBPC3-targeted knock-in mice.

Epigallocatechin-3-Gallate Accelerates Relaxation and Ca2+ Transient Decay and Desensitizes Myofilaments in Healthy and Mybpc3-Targeted Knock-in Cardiomyopathic Mice

“…The faster time to peak Ca 2+ is probably due to EGCg effects on the ryanodine receptor. Indeed, it has been shown that EGCg activates the ryanodine receptor at 10 nM in sarcoplasmic reticulum (SR) vesicles isolated from rabbit left ventricles (Feng et al, 2012) and in the range of 1 nM–20 μM in junctional SR vesicles isolated from skeletal muscle (Najafi et al, 2015). At a concentration of 1.8 μM, EGCg had no effect on PLB Ser16/Thr17 phosphorylation (Supplemental Figure 1).…”

“…Data from canine SR vesicles and HEK293 cell microsomes show that EGCg concentrations > 4.8 μM directly inhibit SR calcium ATPase (Kargacin et al, 2011). Additionally, Feng et al reported no effect on SERCA in rabbit cardiac and skeletal SR membranes with 1–2 μM EGCg (Feng et al, 2012; Najafi et al, 2015). We therefore rule out that the acceleration of relaxation kinetics in the presence of 1.8 μM EGCg is due to an increased SERCA activity.…”

“…The Mybpc3 KI cardiomyopathy mouse model was generated by the targeted insertion of a G > A transition on the last nucleotide of exon 6 and maintained on the Black Swiss background (Vignier et al, 2009; Fraysse et al, 2012; Schlossarek et al, 2012, 2014; Gedicke-Hornung et al, 2013; Mearini et al, 2013, 2014; Stöhr et al, 2013; Friedrich et al, 2014; Najafi et al, 2015; Thottakara et al, 2015; Flenner et al, 2016). This study was carried out in accordance with the recommendations of the guide for the care and use of laboratory animals published by the NIH (Publication No.…”

The Importance of Biological Sex and Estrogen in Rodent Models of Cardiovascular Health and Disease

“…198 In another model of HCM, in which mice carry a point mutation in myosin-binding protein C, isolated cardiomyocytes and myofilaments from male animals exhibited reduced maximal force generating capacity compared to females. 199 …”

Sexually dimorphic myofilament function in a mouse model of nemaline myopathy

“…Indeed, by using transgenic mouse models carrying either the R403Q MyHC mutation or a mutation in the cardiac myosin-binding protein C, it has been demonstrated that the maximal steady-state isometric force and Ca 2+ sensitivity of cardiomyocytes was different between males and females probably because of distinguishable phosphorylated states of proteins such as cardiac troponin I [22,23].…”