14 February 2020 | News
Data show that cardiac dysfunction in muscular dystrophy-associated cardiomyopathy occurs at the cellular cardiomyocyte level
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In a study recently published in Nature Communications, scientists at Japan based Okayama University describe the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy.
Heart failure is the major cause of death for muscular dystrophy patients; however little is known for the molecular mechanism of muscular dystrophy-associated cardiomyopathy. In this study, a research team spearheaded by Senior Lecturer KATANOSAKA Yuki at Okayama University demonstrate for the first time the cellular and molecular pathomechanisms of muscular dystrophy-associated cardiomyopathy using mouse models of Fukuyama muscular dystrophy with a deficiency for the fukutin gene (Fktn), which encodes a Golgi-based ribitol-phosphate transferase that catalyzes the biosynthesis of tandem ribitol-phosphate structure on α-dystroglycans (DG). As DG and proteins of the dystrophin–glycoprotein complex provide structural support for the sarcolemma in muscle tissue, a loss of membrane fragility was thought to be a cause for cardiac dysfunction in these diseases collectively known as α-DGpathies. However, their data show that cardiac dysfunction in muscular dystrophy-associated cardiomyopathy occurs at the cellular cardiomyocyte level.
In this study, although cardiac Fktn elimination markedly reduced α-DG glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. Younger Fktn-deficient mice show a vulnerability to hemodynamic stress conditions via impaired compensative hypertrophic response of cardiomyocytes. Adult Fktn-deficient mice exhibit altered cardiac morphology and dysfunction, suggesting that FKTN is critical for maintaining contractile function of individual cardiomyocytes.
In addition, the team shows that acute Fktn-elimination causes the disordered Golgi-microtubule network in myocytes. Finally, the team shows that treatment with colchicine (an FDA-approved drug for the treatment of familial Mediterranean fever) improved cardiac dysfunction of Fktn-deficient hearts via the recovery of myocyte shortening, which may open a new avenue for therapeutic strategies.