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

  • Molecular and cellular mechanisms of disease
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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/m2) compared to corresponding WT (18.4 ± 1.8 kN/m2) 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 Ca2+-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.

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Acknowledgments

We are grateful to Nicky Boontje for valuable technical support and laboratory assistance.

Grant

We acknowledge support from the Netherlands organization for scientific research (NWO; VIDI grant 91711344), the 7th Framework Program of the European Union (“BIG-HEART”, grant agreement 241577), and from ICIN-Netherlands Heart Institute.

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Correspondence to Aref Najafi.

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Figure 1

LV weight normalized for body weight remained unchanged in WT male and female sedentary and exercised mice (A). In contrast, exercised resulted in a significantly higher LV weight in HET mice (B, Pexercise < 0.05 and Pinteraction < 0.05 in 2-way ANOVA), while no changes were observed in male HET exercised mice. †P < 0.05 female vs. male; §P < 0.05 exercised vs. corresponding sedentary mice; #Pinteraction < 0.05 in 2-way ANOVA. (DOC 529 kb)

Figure 2

Weekly running distance and total distance ran over a period of 8 weeks in male (A) and female mice (B). Female HET mice ran a significantly longer distance compared to HET male and WT female mice (C, Pgenotype < 0.05 and Psex < 0.05 in 2-way ANOVA). No correlation was detected between running distance and LV weight in exercised groups (D). At the first week of exercise protocol a significant higher distance was detected at day six and seven in HET female compared with male counterparts (E, Psex < 0.05 and Pdays < 0.05 in 2-way ANOVA). *P < 0.05 HET vs. WT; †P < 0.05 female vs. male. (DOC 504 kb)

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Najafi, A., Schlossarek, S., van Deel, E.D. et al. Sexual dimorphic response to exercise in hypertrophic cardiomyopathy-associated MYBPC3-targeted knock-in mice. Pflugers Arch - Eur J Physiol 467, 1303–1317 (2015). https://doi.org/10.1007/s00424-014-1570-7

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