The dystrophin–glycoprotein complex (DGC) links the intracellular cytoskeleton to the extracellular basement membrane, thereby providing structural support for the sarcolemma. Many patients with muscular dystrophies, particularly those with defects in cardiomyopathies with chamber dilation and myocardial dysfunction. Heart failure is the major cause of death for muscular dystrophy patients; however, the molecular pathomechanism remains unknown. Here, I show the detailed molecular pathogenesis of muscular dystrophy–associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced the glycosylation of α-dystroglycan and the expression of DGC proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that the physiological contribution of DGC proteins in the heart increases after 6 mo of age. In addition, Fktn-deficient mice maintain normal cardiac function at young age, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. Young Fktn-deficient mice did not show a compensative hypertrophic response to hemodynamic stress and quickly developed heart failure with chamber dilation and contractile dysfunction. In these mice, Ca2+-calcineurin signaling was already elevated under physiological conditions, and MEF2-HDAC axes essential for the hypertrophic response were unable to function under stress conditions. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi–microtubule networks, which were ameliorated with colchicine treatment. Microarray analysis in control and Fktn-deficient hearts suggest that elimination of Fktn impacts the expression profile of Golgi-related genes, and that the pathological mechanism of cardiac dysfunction induced by Fktn elimination partly overlaps with that of neurodegenerative disease. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and, thus, the results may lead to strategies for intervention.
Reduced plasticity and microtubule densification in muscular dystrophy-related cardiomyopathy: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle
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Yuki Katanosaka; Reduced plasticity and microtubule densification in muscular dystrophy-related cardiomyopathy: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle. J Gen Physiol 5 September 2022; 154 (9): e2021ecc45. doi: https://doi.org/10.1085/jgp.2021ecc45
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