The ␣7␤1 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 ␣7␤1 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 ␣7␤1 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 ␣7␤1 integrin, dystrophin, and utrophin complexes act in a concerted manner to maintain the structural and functional integrity of skeletal muscle. (Am J Pathol