Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

• Published in: Nature communications 2019-12, Vol.10 (1), p.5754-17, Article 5754
• Main Authors: Ujihara, Yoshihiro, Kanagawa, Motoi, Mohri, Satoshi, Takatsu, Satomi, Kobayashi, Kazuhiro, Toda, Tatsushi, Naruse, Keiji, Katanosaka, Yuki
• Format: Article
• Language: English
• Subjects: 13; 13/1; 14; 14/19; 14/34; 38; 38/61; 45; 59; 631/45/612/1231; 64; 64/60; 692/4019/592/75/74/1540; 692/617/375/374; 82/51; Adult; Age Factors; Animals; Animals, Newborn; Cells, Cultured; Colchicine; Congestive heart failure; CRISPR-Cas Systems - genetics; Disease Models, Animal; Dystroglycans - metabolism; Dystrophy; FCMD protein; Female; Gene Knockout Techniques; Glycosylation; Heart failure; Heart Failure - etiology; Heart Failure - pathology; Heart Ventricles - cytology; Heart Ventricles - pathology; HEK293 Cells; Humanities and Social Sciences; Humans; Male; Membrane Proteins - genetics; Mice; Mice, Knockout; multidisciplinary; Muscle, Skeletal - cytology; Muscle, Skeletal - pathology; Muscular Dystrophies - complications; Muscular Dystrophies - genetics; Muscular Dystrophies - pathology; Muscular dystrophy; Mutation; Myocardial Contraction - genetics; Myocytes, Cardiac - cytology; Myocytes, Cardiac - pathology; Primary Cell Culture; Sarcolemma - pathology; Science; Science (multidisciplinary); Transferases - genetics; Transferases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13623-2

Heart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we 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 α-dystroglycan 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. During young adulthood, Fktn -deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. 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. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention. Mutations in Ftkn cause Fukuyama muscular dystrophy, and heart failure is the main cause of death in thes patients. Here the authors show that acute elimination of Fktn in adult mice causes early mortality, and this is associated with myocyte dysfunction, with disorganised Golg-microtubule networks, and that the pathology can be ameliorated with colchicine treatment.