TY - JOUR TI - Thrombospondin expression in myofibers stabilizes muscle membranes AU - Vanhoutte, Davy AU - Schips, Tobias G AU - Kwong, Jennifer Q AU - Davis, Jennifer AU - Tjondrokoesoemo, Andoria AU - Brody, Matthew J AU - Sargent, Michelle A AU - Kanisicak, Onur AU - Yi, Hong AU - Gao, Quan Q AU - Rabinowitz, Joseph E AU - Volk, Talila AU - McNally, Elizabeth M AU - Molkentin, Jeffery D A2 - Wagers, Amy J VL - 5 PY - 2016 DA - 2016/09/26 SP - e17589 C1 - eLife 2016;5:e17589 DO - 10.7554/eLife.17589 UR - https://doi.org/10.7554/eLife.17589 AB - Skeletal muscle is highly sensitive to mutations in genes that participate in membrane stability and cellular attachment, which often leads to muscular dystrophy. Here we show that Thrombospondin-4 (Thbs4) regulates skeletal muscle integrity and its susceptibility to muscular dystrophy through organization of membrane attachment complexes. Loss of the Thbs4 gene causes spontaneous dystrophic changes with aging and accelerates disease in 2 mouse models of muscular dystrophy, while overexpression of mouse Thbs4 is protective and mitigates dystrophic disease. In the myofiber, Thbs4 selectively enhances vesicular trafficking of dystrophin-glycoprotein and integrin attachment complexes to stabilize the sarcolemma. In agreement, muscle-specific overexpression of Drosophila Tsp or mouse Thbs4 rescues a Drosophila model of muscular dystrophy with augmented membrane residence of βPS integrin. This functional conservation emphasizes the fundamental importance of Thbs’ as regulators of cellular attachment and membrane stability and identifies Thbs4 as a potential therapeutic target for muscular dystrophy. KW - intracellular trafficking KW - thrombospondin KW - Muscular Dystrophy JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -