Thrombospondin expression in myofibers stabilizes muscle membranes
- University of Cincinnati, United States
- Emory University, United States
- Northwestern University, United States
- Temple University School of Medicine, United States
- Weizmann Institute of Science, Israel
Abstract
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.
Article and author information
Author details
Jeffery D Molkentin
Funding
Howard Hughes Medical Institute (Molkentin)
- Jeffery D Molkentin
National Institutes of Health (award P01NS072027)
- Jeffery D Molkentin
National Institutes of Health (award R01HL105924)
- Jeffery D Molkentin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Amy J Wagers, Harvard University, United States
Ethics
Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee of the Cincinnati Children's Hospital Medical Center (Protocol# IACUC2013-0013). No human subjects or human tissue was directly used in experiments in this study.
Version history
- Received: May 6, 2016
- Accepted: September 21, 2016
- Accepted Manuscript published: September 26, 2016 (version 1)
- Version of Record published: October 13, 2016 (version 2)
Copyright
© 2016, Vanhoutte et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Thrombospondin expression in myofibers stabilizes muscle membranes
eLife 5:e17589.
https://doi.org/10.7554/eLife.17589
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