Integrins: Redundant or Important Players in Skeletal Muscle?

Abstract

dystrophin glycoprotein complex congenital muscular dystrophy Duchenne muscular dystrophy myotendinous junction neuromuscular junction embryonic stem Migration of myogenic cells from the somites and their subsequent fusion to myotubes are key steps during skeletal muscle development. Continuous interaction of the cells with the neighborhood most likely triggers all events necessary to induce the genetic programs for differentiation, migration, and fusion into multinucleated myotubes. Likewise, it is well recognized that the function and the maintenance of tissue integrity are dependent on specific interactions of cells with the surrounding extracellular matrix. Transmembrane receptors are involved in polymerization and assembly of the matrix (1Henry M.D. Campbell K.P. Cell. 1998; 95: 859-870Abstract Full Text Full Text PDF PubMed Scopus (342) Google Scholar, 2Sasaki T. Forsberg E. Bloch W. Addicks K. Fässler R. Timpl R. Exp. Cell Res. 1998; 238: 70-81Crossref PubMed Scopus (57) Google Scholar) and in addition provide both a mechanical link to the cytoskeleton and a means of transducing signals from the extracellular matrix to the nucleus (3Sastry S.K. Horwitz A.F. Curr. Opin. Cell Biol. 1993; 5: 819-831Crossref PubMed Scopus (410) Google Scholar, 4Schwartz M.A. Trends Cell Biol. 2001; 11: 466-470Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). In skeletal muscle two major types of extracellular-cytoskeletal linkages exist at the cell plasma membrane. Numerous studies over the past decade have addressed the function of the dystrophin-glycoprotein complex (DGC).1 Insights into the biological significance of integrin receptors for skeletal muscle development and function have been gained more recently, largely by gene targeting approaches and analyses of human diseases caused by integrin mutations. This review will therefore focus mainly on recent advances in understanding of the function of integrins in skeletal muscle. Integrins form the major family of cell surface adhesion receptors, mediating both cell-cell and cell-matrix interactions. They are heterodimeric, transmembrane glycoproteins consisting of an α and a β chain that are non-covalently associated (5Hynes R.O. Cell. 1992; 69: 11-25Abstract Full Text PDF PubMed Scopus (9026) Google Scholar). To date, 18 α and 8 β chains have been identified, and these combine in a restricted manner to form at least 24 different dimers (6van der Flier A. Sonnenberg A. Cell Tissue Res. 2001; 305: 285-298Crossref PubMed Scopus (818) Google Scholar). Integrin diversity is increased still further through the expression of intra- and extracellular splice variants for several subchains. Among these, the β1 integrin family forms the largest group of receptors for extracellular matrix proteins. So far, most conclusions about function and expression of integrins in vertebrate skeletal muscle have been drawn from combined studies in human, rat, mouse, chicken, and quail, mainly utilizing in vitro approaches. It is difficult from these studies to evaluate the precise function of integrins at the tissue level, as some integrins have only been detected in one species but not in others (7Mcdonald K.A. Horwitz A.F. Knudsen K.A. Semin. Dev. Biol. 1995; 6: 105-116Crossref Scopus (37) Google Scholar). Of the 12 current members of the β1 integrin family, a subset has been shown convincingly to be expressed in mammalian at focal contacts, costameres, neuromuscular (NMJ) and myotendinous junctions (MTJ), or the sarcolemmal membrane during either muscle development or in the adult (Fig.1). Studies performed in avian have indicated that β1integrins are involved in cell migration from the somite (8Jaffredo T. Horwitz A.F. Buck C.A. Rong P.M. Dieterlen-Lievre F. Development. 1988; 103: 431-446PubMed Google Scholar) and terminal differentiation of myoblasts into myotubes (9Menko A.S. Boettiger D. Cell. 1987; 51: 51-57Abstract Full Text PDF PubMed Scopus (310) Google Scholar). In vitro studies in avian and rodent species imply that the α4 integrins, containing either the β1 or β7 subunit, and αv, α5β1, α6β1, and α7β1 integrins are the major players in muscle differentiation. These integrin chains are readily detected in myoblasts. The α4 integrins were thought to be of particular importance providing the major cell-cell contact for myotube formation during secondary myogenesis through a heterophilic interaction with the counter-receptor VCAM-1 (10Rosen G.D. Sanes J.R. LaChance R. Cunningham J.M. Roman J. Dean D.C. Cell. 1992; 69: 1107-1119Abstract Full Text PDF PubMed Scopus (316) Google Scholar). However, chimeric mice with a high percentage of α4-deficient embryonic stem (ES) cells formed normal muscle (11Yang J.T. Rando T.A. Mohler W.A. Rayburn H. Blau H.M. Hynes R.O. J. Cell Biol. 1996; 135: 829-835Crossref PubMed Scopus (58) Google Scholar). These data, together with the demonstration that, in vitro, α4-deficient myoblasts can form myotubes strongly suggests that α4-