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Cardiac manifestations of inherited metabolic disease linked to cellular metabolism of vitamin B12 : study in two murine models of invalidation of Mtr and MMACHC genes

Abstract : Heart failure is one of the most common causes of morbidity and mortality in Western countries and its incidence is increasing in developing countries. Deficiency in folates and vitamin B12 (cobalamin) during gestation and lactation causes a fetal programming effect with metabolic cardiomyopathy related to decreased synthesis of methionine and impaired remethylation (RM) of homocysteine. Inborn errors of cobalamin metabolism, including CblG caused by mutations of MTR gene, which encodes methionine synthase (that catalyzes vitamin B12 dependent remethylation of homocysteine to methionine), and CblC caused by mutations of MMACHC gene cause cardiometabolic decompensation in infants. However, cardiac consequences and mechanisms underlying this process in adults are unknown. The aim of this Ph.D. project was to investigate the cardiac functional, metabolic and molecular consequences of the inhibition of methionine synthesis in transgenic mouse model of constitutive cardiac specific invalidation of Mtr gene and systemic invalidation of MMACHC gene. We found that the selective Mtr invalidation in the heart produces cardiomyopathy with heart failure, myocardium hypertrophy and systolic dysfunction in young adult mice. At the tissue and molecular levels, the observed cardiomyopathy was related to impaired energy metabolism with disruption of fatty acid oxidation and oxidative phosphorylation, cellular stress and cardiac remodeling with fibrosis. Impaired energy metabolism was linked to decreased expression of Sirt3. The mislocalization and nuclear sequestration of hnRNPA1 could explain part of the expression changes of genes and proteins. These findings suggest a further need to evaluate whether CblG could be a new genetic cause of primary heart failure in adult patients.
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Submitted on : Friday, June 19, 2020 - 11:02:40 AM
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Viola Jepchumba Kosgei. Cardiac manifestations of inherited metabolic disease linked to cellular metabolism of vitamin B12 : study in two murine models of invalidation of Mtr and MMACHC genes. Biochemistry, Molecular Biology. Université de Lorraine, 2019. English. ⟨NNT : 2019LORR0319⟩. ⟨tel-02874823⟩

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