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Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice

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Abstract

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric septal hypertrophy and is often caused by mutations in MYBPC3 gene encoding cardiac myosin-binding protein C. In contrast to humans, who are already affected at the heterozygous state, mouse models develop the phenotype mainly at the homozygous state. Evidence from cell culture work suggested that altered proteasome function contributes to the pathogenesis of HCM. Here we tested in two heterozygous Mybpc3-targeted mouse models whether adrenergic stress unmasks a specific cardiac phenotype and proteasome dysfunction. The first model carries a human Mybpc3 mutation (Het-KI), the second is a heterozygous Mybpc3 knock-out (Het-KO). Both models were compared to wild-type (WT) mice. Mice were treated with a combination of isoprenaline and phenylephrine (ISO/PE) or NaCl for 1 week. Whereas ISO/PE induced left ventricular hypertrophy (LVH) with increased posterior wall thickness to a similar extent in all groups, it increased septum thickness only in Het-KI and Het-KO. ISO/PE did not affect the proteasomal chymotrypsin-like activity or β5-subunit protein level in Het-KO or wild-type mice (WT). In contrast, both parameters were markedly lower in Het-KI and negatively correlated with the degree of LVH in Het-KI only. In conclusion, adrenergic stress revealed septal hypertrophy in both heterozygous mouse models of HCM, but proteasome dysfunction only in Het-KI mice, which carry a mutant allele and closely mimic human HCM. This supports the hypothesis that proteasome impairment contributes to the pathophysiology of HCM.

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Acknowledgments

We thank X.J. Wang (University of South Dakota) for the antibody directed against the β5-subunit of the proteasome. This work was supported by the sixth and seventh Framework Programs of the European Union (Marie Curie EXT-014051; Health-F2-2009-241577; Big-Heart project), the Deutsche Forschungsgemeinschaft (FOR-604-CA 618/1-1 and 1-2), and the Leducq Foundation (Research grant Nr. 11, CVR 04).

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  1. Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

    Saskia Schlossarek, Friederike Schuermann, Birgit Geertz, Giulia Mearini, Thomas Eschenhagen & Lucie Carrier

  2. Inserm U974, 75013, Paris, France

    Lucie Carrier

  3. University Pierre et Marie Curie-Paris6, UMR-S974, CNRS UMR7215, Institut de Myologie, IFR14, 75013, Paris, France

    Lucie Carrier

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  1. Saskia Schlossarek
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  2. Friederike Schuermann
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  4. Giulia Mearini
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  5. Thomas Eschenhagen
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Correspondence to Lucie Carrier.

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Schlossarek, S., Schuermann, F., Geertz, B. et al. Adrenergic stress reveals septal hypertrophy and proteasome impairment in heterozygous Mybpc3-targeted knock-in mice. J Muscle Res Cell Motil 33, 5–15 (2012). https://doi.org/10.1007/s10974-011-9273-6

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