Journal Article

Thrombospondin-3 augments injury-induced cardiomyopathy by intracellular integrin inhibition and sarcolemmal instability

Khalil, Hadi, Karch, Jason, Maillet, Marjorie, Molkentin, Jeffery D., Vo, Alexander, Brody, Matthew J., Ross, Robert S., Vanhoutte, Davy, Tjondrokoesoemo, Andoria, Correll, Robert N., Schips, Tobias G., Sargent, Michelle A.

2019

Overview

Thrombospondins (Thbs) are a family of five secreted matricellular glycoproteins in vertebrates that broadly affect cell-matrix interaction. While Thbs4 is known to protect striated muscle from disease by enhancing sarcolemmal stability through increased integrin and dystroglycan attachment complexes, here we show that Thbs3 antithetically promotes sarcolemmal destabilization by reducing integrin function, augmenting disease-induced decompensation. Deletion of Thbs3 in mice enhances integrin membrane expression and membrane stability, protecting the heart from disease stimuli. Transgene-mediated overexpression of α7β1D integrin in the heart ameliorates the disease predisposing effects of Thbs3 by augmenting sarcolemmal stability. Mechanistically, we show that mutating Thbs3 to contain the conserved RGD integrin binding domain normally found in Thbs4 and Thbs5 now rescues the defective expression of integrins on the sarcolemma. Thus, Thbs proteins mediate the intracellular processing of integrin plasma membrane attachment complexes to regulate the dynamics of cellular remodeling and membrane stability. Thrombospondin 4 has been shown to protect the heart and the skeletal muscle by enhancing matrix secretion and membrane stability thanks to its intracellular function. Here the authors show that thrombospondin 3 exacerbates injury-induced cardiomyopathy and promotes destabilization of the cardiomyocyte membrane by impairing integrin trafficking to the sarcolemma.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/41 / 631/80/79/1236 / 64 / 64/60 / 692/4019/592/75/230 / 96/106 / Animals / Cardiomyocytes / Cardiomyopathies - diagnostic imaging / Cardiomyopathies - etiology / Cardiomyopathies - pathology / Cardiomyopathy / Cells, Cultured / Chlorocebus aethiops / Clonal deletion / Coronary artery disease / COS Cells / Destabilization / Disease Models, Animal / Dynamic stability / Dystroglycan / Dystroglycans - metabolism / Echocardiography / Female / Glycoproteins / Heart / Heart diseases / Homeostasis / Humanities and Social Sciences / Humans / Integrins / Integrins - metabolism / Intracellular / Kinases / Localization / Male / Membranes / Mice / Mice, Inbred C57BL / Mice, Transgenic / multidisciplinary / Muscles / Musculoskeletal system / Mutation / Myocytes, Cardiac / Pathology / Primary Cell Culture / Protein Interaction Domains and Motifs - genetics / Proteins / Rats / Rats, Sprague-Dawley / Rodents / Sarcolemma / Sarcolemma - metabolism / Sarcolemma - pathology / Science / Science (multidisciplinary) / Skeletal muscle / Stability / Stability augmentation / Thrombospondin / Thrombospondins - genetics / Thrombospondins - metabolism / Transgenic animals / Vertebrates