Matriglycan maintains t- tubule structural integrity in cardiac muscle

• 成果类型: Article
• 署名作者: Hord, Jeffrey M.; Anderson, Mary E.; Prouty, Sally J.; Melton, Shelly; Gastel, Zeita; Zimmerman, Kathy; Weiss, Robert M.; Campbell, Kevin P.
• 署名单位: Howard Hughes Medical Institute; University of Iowa; University of Iowa; University of Iowa; University of Iowa; University of Iowa; University of Iowa; US Department of Veterans Affairs; Veterans Health Administration (VHA); Iowa City VA Health Care System; University of Iowa
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12818
• DOI: 10.1073/pnas.2402890121
• 发表日期: 2024-05-28
• 关键词: dystrophin-glycoprotein complex; transverse-tubules; reduced synchrony; ca2+ release; dystroglycan; disruption; maturation; membrane; junctophilin-2; deficiency

摘要

Maintaining the structure of cardiac membranes and membrane organelles is essential for heart function. A critical cardiac membrane organelle is the transverse tubule system (called the t - tubule system) which is an invagination of the surface membrane. unique structural characteristic of the cardiac muscle t - tubule system is the extension of the extracellular matrix (ECM) from the surface membrane into the t - tubule lumen. However, the importance of the ECM extending into the cardiac t - tubule lumen is not well understood. Dystroglycan (DG) is an ECM receptor in the surface membrane many cells, and it is also expressed in t - tubules in cardiac muscle. Extensive posttranslational processing and O - glycosylation are required for DG to bind ECM proteins and the binding is mediated by a glycan structure known as matriglycan. Genetic disruption resulting in defective O - glycosylation of DG results in muscular dystrophy with cardiorespiratory pathophysiology. Here, we show that DG is essential for maintaining cardiac t - tubule structural integrity. Mice with defects in O - glycosylation of DG developed normal t - tubules but were susceptible to stress - induced t - tubule loss or severing that contributed to cardiac dysfunction and disease progression. Finally, we observed similar stress - induced cardiac t - tubule disruption in a cohort of mice that solely lacked matriglycan. Collectively, our data indicate that DG in t - tubules anchors the luminal ECM to the t - tubule membrane via the polysaccharide matriglycan, which is critical to transmitting structural strength of the ECM to the t - tubules and provides resistance to mechanical stress, ultimately preventing disruptions in cardiac t - tubule integrity.