Secondary reduction of alpha 7B integrin in laminin alpha 2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle

The integrins are a large family of heterodimeric transmembrane cellular re ceptors which mediate the association between the extracellular matrix (ECM ) and cytoskeletal proteins. The alpha 7 beta 1 integrin is a major laminin binding integrin in skeletal and cardiac muscle and is thought to be invol ved in myogenic differentiation and migration processes. The main binding p artners of the alpha 7 integrin are laminin-l (alpha 1-beta 1-gamma 1), lam inin-2 (alpha 2-beta 1-gamma 1) and laminin-4 (alpha 2-beta 2-gamma 1). Tar geted deletion of the gene for the alpha 7 integrin subunit (ITGA7) in mice leads to a novel form of muscular dystrophy. In the present study we have investigated the expression of two alternative splice variants, the alpha 7 B and beta 1D integrin subunits, in normal human skeletal muscle, as well a s in various forms of muscular dystrophy. In normal human skeletal muscle t he expression of the alpha 7 integrin subunit appeared to be developmentall y regulated: it was first detected at 2 years of age. Ln contrast, the beta 1D integrin could be detected in immature and mature muscle in the sarcole mma of normal fetal skeletal muscle at 18 weeks gestation. The expression o f alpha 7B integrin was significantly reduced at the sarcolemma in six pati ents with laminin alpha 2 chain deficient congenital muscular dystrophy (CM D) (age >2 years). However, this reduction was not correlated with the amou nt of laminin alpha 2 chain expressed. In contrast, the expression of the l aminin a2 chain was not altered in the skeletal muscle of the alpha 7 knock -out mice. These data argue in favor that there is not a tight correlation between the expression of the alpha 7 integrin subunit and that of the lami nin alpha 2 chain in either human or murine dystrophic muscle. Interestingl y, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of alpha 7B was upregulated irrespective of the level of dystrop hin expression as shown by a strong sarcolemmal staining pattern even in yo ung boys (age <2 years). The expression of the beta 1D integrin subunit was not altered in any of our patients with different types of muscular dystro phy. In contrast, sarcolemmal expression of beta 1D integrin was significan tly reduced in the alpha 7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of alpha 7 B in laminin alpha 2 chain deficiency defines a biochemical change in the c omposition of the plasma membrane resulting from a primary protein deficien cy in the basal lamina. These findings, in addition to the occurrence of a muscular dystrophy in alpha 7 deficient mice, implies that the alpha 7B int egrin is an important laminin receptor within the plasma membrane which pla ys a significant role in skeletal muscle function and stability. (C) 1999 E lsevier Science B.V. All rights reserved.