Myotendinous Junction Defects and Reduced Force Transmission in Mice that Lack α7 Integrin and Utrophin

Abstract

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

Age-related changes in structure and extracellular matrix protein expression levels in rat tendons

“…While PRG4, Eln, SDF1, and TGFb1 were clearly localized to the tendon side of the MTJs, CTGF was localized to the ends of the skeletal muscle fibers embedded into tendons. It is well known that muscle fibers secrete specialized proteins at the MTJs (Law et al 1994;Jarvinen et al 2003;Welser et al 2009), but to our knowledge, the present study is the first to show that tenocytes located in close proximity to the MTJs also participate in defining structural composition of the MTJs by increased deposition of the specific proteins.…”

“…A number of proteins are reported to be specifically expressed or to show increased levels at the MTJs (Law et al 1994;Jarvinen et al 2003;Welser et al 2009). Consistent with previous reports (Turner et al 1991;Frenette and Tidball 1998;Koch et al 2004), we confirmed paxillin, talin, and collagen XXII localization to the muscle side of the MTJs.…”

Knockdown of col22a1 gene in zebrafish induces a muscular dystrophy by disruption of the myotendinous junction

“…In addition to myoseptal defects, a strong reduction of sarcolemma folds at the MTJ was observed in col22a1 morphants, as reported in mice models for muscular dystrophy, such as in itga7-null mice (Miosge et al, 1999), mdx mice (Law and Tidball, 1993;Law et al, 1995) and the double mutants mdx/itga7 −/− and itga7/utr −/− (utrophin) (Rooney et al, 2006;Welser et al, 2009), but not reported in any of the zebrafish dystrophic class mutants. Reduction of MTJ folds and lack of myoseptal stiffness may also compromise force transmission and likely contributed to fragile muscle attachments.…”

“…The impact of these mutations in MTJ formation and/or function is still poorly documented, particularly in the context of human diseases. However, mice that lack dystrophin (mdx; Dmd -Mouse Genome Informatics) (Law and Tidball, 1993;Law et al, 1995), laminin α2 (dy; Lama2 -Mouse Genome Informatics) (Desaki, 1992) or integrin α7 (Miosge et al, 1999;Welser et al, 2009) exhibit a striking reduction in the number of membrane folds at MTJ that impairs its function and results in progressive muscular dystrophy.…”

Hanging on for the ride: Adhesion to the extracellular matrix mediates cellular responses in skeletal muscle morphogenesis and disease

“…It was hypothesized that upregulation of the UGC and Integrin receptors could be compensating for the disrupted DGC. Indeed, phenotypes are more severe in mdx/Itga7 (Guo et al, 2006; Rooney et al, 2006) , mdx/utr (Deconinck et al, 1997; Grady et al, 1997), and utr/Itga7 (Welser et al, 2009) double mutants. Critically, the background strain of mouse on which the mdx mutation was placed had a central role in the ability of the muscle to maintain itself (Fukada et al, 2010), with the DBA/2J strain exhibiting greatly decreased satellite cell renewal potential.…”