ABSTRACT
Hypertrophic cardiomyopathy is the most common cardiovascular disease, which is characterized by structural and functional myocardial abnormalities. It is caused predominantly by autosomal dominant mutations, mainly in genes encoding cardiac sarcomeric proteins, resulting in diverse phenotypical patterns and a heterogenic clinical course. Unconventional myosin VI (MVI) is one of the proteins important for heart function, as it was shown that a point mutation within MYO6 is associated with left ventricular hypertrophy. Previously, we showed that MVI is expressed in the cardiac muscle, where it localizes to the sarcoplasmic reticulum and intercalated discs. Here, we addressed the mechanisms of its involvement in cardiac dysfunction in Snell's waltzer mice (natural MVI knockouts) during heart development. We showed that heart enlargement was already seen in the E14.5 embryos and newborn animals (P0), and was maintained throughout the examined lifespan (up to 12 months). The higher levels of MVI were observed in the hearts of E14.5 embryos and P0 of control heterozygous mice. A search for the mechanisms behind the observed phenotype revealed several changes, accumulation of which resulted in age-progressing heart dysfunction. The main changes that mostly contribute to this functional impairment are the increase in cardiomyocyte proliferation in newborns, disorganization of intercalated discs, and overexpression of SERCA2 in hearts isolated from 12-month-old mice, indicative of functional alterations of sarcoplasmic reticulum. Also, possible aberrations in the heart vascularization, observed in 12-month-old animals could be additional factors responsible for MVI-associated heart dysfunction.
