Published online before print September 3, 2009

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(American Journal of Pathology. 2009;175:1545-1554.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090052

Myotendinous Junction Defects and Reduced Force Transmission in Mice that Lack 7 Integrin and Utrophin

Jennifer V. Welser^*, Jachinta E. Rooney^*, Nicolette C. Cohen^*, Praveen B. Gurpur^*, Cherie A. Singer^*, Rebecca A. Evans, Bryan A. Haines and Dean J. Burkin^*

From the Department of Pharmacology,^* University of Nevada School of Medicine, Reno; and the Nevada Transgenic Center, University of Nevada School of Medicine, Reno, Nevada

The 7β1 integrin, dystrophin, and utrophin glycoprotein complexes are the major laminin receptors in skeletal muscle. Loss of dystrophin causes Duchenne muscular dystrophy, a lethal muscle wasting disease. Duchenne muscular dystrophy-affected muscle exhibits increased expression of 7β1 integrin and utrophin, which suggests that these laminin binding complexes may act as surrogates in the absence of dystrophin. Indeed, mice that lack dystrophin and 7 integrin (mdx/7^–/–), or dystrophin and utrophin (mdx/utr^–/–), exhibit severe muscle pathology and die prematurely. To explore the contribution of the 7β1 integrin and utrophin to muscle integrity and function, we generated mice lacking both 7 integrin and utrophin. Surprisingly, mice that lack both 7 integrin and utrophin (7/utr^–/–) were viable and fertile. However, these mice had partial embryonic lethality and mild muscle pathology, similar to 7 integrin-deficient mice. Dystrophin levels were increased 1.4-fold in 7/utr^–/– skeletal muscle and were enriched at neuromuscular junctions. Ultrastructural analysis revealed abnormal myotendinous junctions, and functional tests showed a ninefold reduction in endurance and 1.6-fold decrease in muscle strength in these mice. The 7/utr^–/– mouse, therefore, demonstrates the critical roles of 7 integrin and utrophin in maintaining myotendinous junction structure and enabling force transmission during muscle contraction. Together, these results indicate that the 7β1 integrin, dystrophin, and utrophin complexes act in a concerted manner to maintain the structural and functional integrity of skeletal muscle.