Journal article
Matriglycan maintains t-tubule structural integrity in cardiac muscle
Proceedings of the National Academy of Sciences - PNAS, Vol.121(22), e2402890121
05/28/2024
DOI: 10.1073/pnas.2402890121
PMCID: PMC11145246
PMID: 38771868
Abstract
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. A 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 of many cells, and it is also expressed in t-tubules in cardiac muscle. Extensive posttranslational processing and
-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
-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
-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.
Details
- Title: Subtitle
- Matriglycan maintains t-tubule structural integrity in cardiac muscle
- Creators
- Jeffrey M Hord - University of IowaMary E Anderson - University of IowaSally J Prouty - University of IowaShelly Melton - University of IowaZeita Gastel - University of IowaKathy Zimmerman - University of IowaRobert M Weiss - University of IowaKevin P Campbell - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.121(22), e2402890121
- DOI
- 10.1073/pnas.2402890121
- PMID
- 38771868
- PMCID
- PMC11145246
- eISSN
- 1091-6490
- Grant note
- P50NS053672 / HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) RO1HL142935 / HHS | National Institutes of Health (NIH) S10OD019941. / HHS | National Institutes of Health (NIH) 5T32HL007121-45 / HHS | National Institutes of Health (NIH) N/A / Howard Hughes Medical Institute (HHMI)
- Language
- English
- Date published
- 05/28/2024
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984628159602771
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