Thrombospondin expression in myofibers stabilizes muscle membranes.
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 theThbs4gene 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 ofDrosophilaTsp or mouse Thbs4 rescues aDrosophilamodel 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.
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Davy
0000-0002-8147-6953
D
Vanhoutte
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Tobias G
TG
Schips
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Jennifer Q
JQ
Kwong
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Jennifer
J
Davis
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Andoria
A
Tjondrokoesoemo
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Matthew J
MJ
Brody
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Michelle A
MA
Sargent
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.
Onur
O
Kanisicak
Robert P. Apkarian Integrated Electron Microscopy Core, Emory University, Atlanta, United States.
Hong
H
Yi
Center for Genetic Medicine, Northwestern University, Chicago, United States.
Quan Q
QQ
Gao
Temple University School of Medicine, Philadelphia, United States.
Joseph E
JE
Rabinowitz
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Talila
T
Volk
Center for Genetic Medicine, Northwestern University, Chicago, United States.
Elizabeth M
EM
McNally
Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States.|Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States.
Jeffery D
0000-0002-3558-6529
JD
Molkentin
D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D015870:Gene Expression; D008566:Membranes / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000503:physiopathology / Q000517:prevention & control; D009210:Myofibrils / Q000378:metabolism*; D019699:Thrombospondins / Q000378:metabolism*
D019699:Thrombospondins; C101864:thrombospondin 4
D. melanogaster; Muscular Dystrophy; cell biology; intracellular trafficking; mouse; thrombospondin
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