Integrins: Redundant or Important Players in Skeletal Muscle?

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-containing integrins are not required to establish the cell-cell contacts necessary for myoblast fusion (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). Whereas α5β1 is the classical fibronectin receptor, both α6β1 and α7β1 are exclusive laminin receptors. α5β1 and α6β1are widely expressed and down-regulated after myotube formation (12Bronner-Fraser M. Artinger M. Muschler J. Horwitz A.F. Development. 1992; 115: 197-211PubMed Google Scholar, 13Blaschuk K.L. Holland P.C. Dev. Biol. 1994; 164: 475-483Crossref PubMed Scopus (35) Google Scholar, 14Boettiger D. Enomoto-Iwamoto M. Yoon H.Y. Hofer U. Menko A.S. Chiquet-Ehrismann R. Dev. Biol. 1995; 169: 261-272Crossref PubMed Scopus (67) Google Scholar), whereas α7β1 is mainly restricted to skeletal and cardiac muscle and strongly up-regulated upon myoblast fusion (15Song W.K. Wang W. Sato H. Bielser D.A. Kaufman S.J. J. Cell Sci. 1993; 106: 1139-1152Crossref PubMed Google Scholar, 16Yao C.C. Ziober B.L. Sutherland A.E. Mendrick D.L. Kramer R.H. J. Cell Sci. 1996; 109: 3139-3150PubMed Google Scholar). The role of α5β1 and α6β1 in muscle development and the reason they coexist at the myoblast stage as ligand-opposing receptors is not yet well defined. Elegant studies by Sastry et al. (17Sastry S.K. Lakonishok M. Thomas D.A. Muschler J. Horwitz A.F. J. Cell Biol. 1996; 133: 169-184Crossref PubMed Scopus (173) Google Scholar), however, suggested distinct functions for both integrins. Overexpression of the α5 subunit in primary quail myoblasts maintained them in a proliferative phase, whereas ectopically expressed α6β1 induced myoblast differentiation (17Sastry S.K. Lakonishok M. Thomas D.A. Muschler J. Horwitz A.F. J. Cell Biol. 1996; 133: 169-184Crossref PubMed Scopus (173) Google Scholar). Given the switch in the muscle cell environment from a fibronectin-rich matrix into a laminin-containing basement membrane with the onset of terminal differentiation (18Kühl U. Öcalan M. Timpl R. von der Mark K. Dev. Biol. 1986; 117: 628-635Crossref PubMed Scopus (92) Google Scholar), these data suggested a fine-tuned regulation of differentiation and matrix assembly via these two integrin receptors. However, no obvious defects in muscle development have been reported either in mice with a targeted deletion of the α6 subunit (19Georges-Labouesse E. Messaddeq N. Yehia G. Cadalbert L. Dierich A. Le Meur M. Nat. Genet. 1996; 13: 370-373Crossref PubMed Scopus (467) Google Scholar) or in myoblasts devoid of α5β1 that efficiently differentiated into myotubes (20Taverna D. Disatnik M.H. Rayburn H. Bronson R.T. Yang J. Rando T.A. Hynes R.O. J. Cell Biol. 1998; 143: 849-859Crossref PubMed Scopus (93) Google Scholar). Various results have implicated α7β1 as the crucial receptor for myoblast migration (21Echtermeyer F. Schöber S. Pöschl E. von der Mark H. von der Mark K. J. Biol. Chem. 1996; 271: 2071-2075Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 22Yao C.C. Ziober B.L. Squillace R.M. Kramer R.H. J. Biol. Chem. 1996; 271: 25598-25603Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 23Crawley S. Farrell E.M. Wang W. Gu M. Huang H.Y. Huynh V. Hodges B.L. Cooper D.N. Kaufman S.J. Exp. Cell Res. 1997; 235: 274-286Crossref PubMed Scopus (63) Google Scholar), and its strong up-regulation in terminally differentiated myotubes further suggested a functional role in this process. Yet, as with other integrin α chain-null mice, skeletal muscle develops normally in the absence of α7β1 (24Mayer U. Saher G. Fässler R. Bornemann A. Echtermeyer F. von der Mark H. Miosge N. Pöschl E. von der Mark K. Nat. Genet. 1997; 17: 318-323Crossref PubMed Scopus (374) Google Scholar). The apparently normal myogenesis in integrin α chain-null mice could be explained by redundancy or overlap in function (25Hynes R.O. Dev. Biol. 1996; 180: 402-412Crossref PubMed Scopus (252) Google Scholar) because integrin β1-inhibiting antibodies, which disrupt the function of all integrins concurrently, perturbed myotube formation in vitro (9Menko A.S. Boettiger D. Cell. 1987; 51: 51-57Abstract Full Text PDF PubMed Scopus (310) Google Scholar). However, a critical role for integrins in muscle development became questionable, when it was demonstrated that skeletal muscle in chimeric mice derived from β1-null ES cells formed normally in vivo, and β1 homozygous mutant myoblasts were shown to be fusion-competent, although differentiation of β1-null ES cells into myotubes was delayed (26Fässler R. Meyer M. Genes Dev. 1995; 9: 1896-1908Crossref PubMed Scopus (615) Google Scholar, 27Hirsch E. Lohikangas L. Gullberg D. Johansson S. Fässler R. J. Cell Sci. 1998; 111: 2397-2409PubMed Google Scholar). These data supported the view that early muscle development is regulated mainly by transcription and growth factors (28Arnold H.H. Braun T. Curr. Top. Dev. Biol. 2000; 48: 129-164Crossref PubMed Scopus (116) Google Scholar), although integrins could be one of the downstream targets. The availability of conditional skeletal muscle-specific β1-integrin knock-out mice, however, has now shed new light on this field of research. Mice lacking β1 integrin specifically in muscle die immediately after birth with only poorly developed muscle fibers. 2M. Schwander and U. Müller, personal communication. At first glance, these data are at odds with earlier results, suggesting that β1 integrins were not required for myogenesis (26Fässler R. Meyer M. Genes Dev. 1995; 9: 1896-1908Crossref PubMed Scopus (615) Google Scholar,27Hirsch E. Lohikangas L. Gullberg D. Johansson S. Fässler R. J. Cell Sci. 1998; 111: 2397-2409PubMed Google Scholar). However, upon closer examination it is apparent that both models differ significantly. In the conditional β1 integrin-null mice, all myoblasts lack β1 integrins, whereas in the chimeric mice, β1-deficient cells are interspersed in a mosaic pattern with wild-type cells. The tight contact between wild-type and mutant cells may commit β1-deficient myoblasts to differentiation, or alternatively, wild-type cells may secrete soluble factors in a β1integrin-dependent manner. This could be sufficient to induce the genetic program in the neighboring β1knock-out cells. Obviously, the conclusions drawn about individual α subunits based on the analysis in chimeric animals have to be reconsidered in view of the impact caused by the environment. Further work will undoubtedly yield important insights into the role of β1 integrins for skeletal muscle differentiation, and the race is on again to determine whether an individual or a combination of integrins underlies the phenotype observed in β1-deficient skeletal muscle. Muscle fibers are surrounded by a basement membrane, composed of the main constituents laminin, collagen IV, the heparan sulfate proteoglycan perlecan, and nidogen-1 (29Timpl R. Brown J.C. Bioessays. 1996; 18: 123-132Crossref PubMed Scopus (585) Google Scholar). Most likely, cell-matrix contact is predominantly maintained through the interaction of muscle cell transmembrane receptors and laminin, the major cell-adhesive protein found in basement membranes. Laminin is a family of ubiquitously expressed heterotrimeric proteins, composed of an α, a β, and a γ chain. The current identification of 14 distinct laminin isoforms is mainly due to the existence of five α (α1–α5), three β (β1–β3), and three γ (γ1–γ3) chains (30Libby R.T. Champliaud M.F. Claudepierre T. Xu Y. Gibbons E.P. Koch M. Burgeson R.E. Hunter D.D. Brunken W.J. J. Neurosci. 2000; 20: 6517-6528Crossref PubMed Google Scholar). In skeletal muscle the α2, α4, and α5 chains have been identified (31Patton B.L. Miner J.H. Chiu A.Y. Sanes J.R. J. Cell Biol. 1997; 139: 1507-1521Crossref PubMed Scopus (375) Google Scholar, 32Ringelmann B. Roder C. Hallmann R. Maley M. Davies M. Grounds M. Sorokin L. Exp. Cell Res. 1999; 246: 165-182Crossref PubMed Scopus (112) Google Scholar, 33Sorokin L.M. Pausch F. Frieser M. Kröger S. Ohage E. Deutzmann R. Dev. Biol. 1997; 189: 285-300Crossref PubMed Scopus (217) Google Scholar). The α4 and α5 chains, however, disappear perinatally from the sarcolemmal membrane and become restricted to the NMJ and blood vessels (31Patton B.L. Miner J.H. Chiu A.Y. Sanes J.R. J. Cell Biol. 1997; 139: 1507-1521Crossref PubMed Scopus (375) Google Scholar, 32Ringelmann B. Roder C. Hallmann R. Maley M. Davies M. Grounds M. Sorokin L. Exp. Cell Res. 1999; 246: 165-182Crossref PubMed Scopus (112) Google Scholar, 33Sorokin L.M. Pausch F. Frieser M. Kröger S. Ohage E. Deutzmann R. Dev. Biol. 1997; 189: 285-300Crossref PubMed Scopus (217) Google Scholar). Laminin-2 (α2β1γ1) and laminin-4 (α2β2γ1) are therefore the major laminin isoforms present throughout muscle development and in the adult, providing the intimate contact between basement membranes and the muscle fibers both at junctional (NMJ and MTJ) and non-junctional areas (34Gullberg D. Tiger T. Cell Sci. 1999; PubMed Scopus Google Scholar). laminin receptors are thought to for skeletal muscle function and laminin isoforms detected in skeletal muscle are recognized by α6β1, and H. Y. N. K. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. N. H. Sonnenberg A. K. J. 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Cell. 1995; Full Text PDF PubMed Scopus Google Scholar). the laminin chain in forms of congenital muscular dystrophy both in human and the H. E. Nat. Genet. 1994; PubMed Scopus Google Scholar, A. H. C. F. J. K. M. K. Nat. Genet. 1995; 11: PubMed Scopus Google Scholar). Integrins provide a link between the cytoskeleton and the extracellular matrix as the and were therefore strong for forms of muscular mice an integrin gene were shown to a but muscular dystrophy after birth (24Mayer U. Saher G. Fässler R. Bornemann A. Echtermeyer F. von der Mark H. Miosge N. Pöschl E. von der Mark K. Nat. Genet. 1997; 17: 318-323Crossref PubMed Scopus (374) Google Scholar). The for muscular were restricted to the muscle and the whereas the muscle fibers in all other were In the human have been identified with a primary integrin from a due to a splice or to E. M. C. S. K. Ziober B.L. Kramer R.H. Kaufman S.J. E. Y. T. Wang E.P. K. Nat. Genet. 1998; PubMed Scopus Google Scholar). The was apparent from birth with delayed in the of and was as congenital no in the could be identified in one with a lack of integrin and of E. M. C. S. K. Ziober B.L. Kramer R.H. Kaufman S.J. E. Y. T. Wang E.P. K. Nat. Genet. 1998; PubMed Scopus Google Scholar). This a in the or in a of the and its identification may yield into the regulation of the The observed in and human are muscle was and human muscle only a The pattern for the laminin chain and of the were (24Mayer U. Saher G. Fässler R. Bornemann A. Echtermeyer F. von der Mark H. Miosge N. Pöschl E. von der Mark K. Nat. Genet. 1997; 17: 318-323Crossref PubMed Scopus (374) Google Scholar, E. M. C. S. K. Ziober B.L. Kramer R.H. Kaufman S.J. E. Y. T. Wang E.P. K. Nat. Genet. 1998; PubMed Scopus Google Scholar). The is in to the of the in human The integrin mice, however, in the of the as are readily the primary of between the muscle and the were in all in these The their and the was from the muscle membrane, suggesting an of function of the (24Mayer U. Saher G. Fässler R. Bornemann A. Echtermeyer F. von der Mark H. Miosge N. Pöschl E. von der Mark K. Nat. Genet. 1997; 17: 318-323Crossref PubMed Scopus (374) Google Scholar, N. C. R. M. U. 1999; Google Scholar). role of integrins for muscle integrity has been reported for integrin and In both the to normally with formed but on the from the cell membrane D.L. Dev. Biol. 1993; PubMed Scopus Google T. J.H. Cell. 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The critical of and the to muscle integrity the as to whether both can for for α7β1 in of and the has been observed U. Saher G. R. der Flier A. Sonnenberg A. Sorokin L. T. J. Sci. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, B.L. Wang W. K. Kaufman S.J. J. Cell Sci. 1997; PubMed Google Scholar, Xu H. L. F. Y. K. J.C. E. J. 1997; PubMed Scopus Google Scholar), although it is still whether this is due to increased transcription E. M. C. S. K. Ziober B.L. Kramer R.H. Kaufman S.J. E. Y. T. Wang E.P. K. Nat. Genet. 1998; PubMed Scopus Google Scholar, B.L. Wang W. K. Kaufman S.J. J. Cell Sci. 1997; PubMed Google Scholar). In of the were in (24Mayer U. Saher G. Fässler R. Bornemann A. Echtermeyer F. von der Mark H. Miosge N. Pöschl E. von der Mark K. Nat. Genet. 1997; 17: 318-323Crossref PubMed Scopus (374) Google Scholar, E. M. C. S. K. Ziober B.L. Kramer R.H. Kaufman S.J. E. Y. T. Wang E.P. K. Nat. Genet. 1998; PubMed Scopus Google Scholar, U. Saher G. R. der Flier A. Sonnenberg A. Sorokin L. T. J. Sci. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). both differ in that and the are for and the integrity of the muscle N. C. R. M. U. 1999; Google Scholar, V. Campbell K.P. J. Cell Biol. 1997; 139: PubMed Scopus Google Scholar). This the that both are receptor and that the to the are The of either however, is as mice lacking dystrophin and α7β1 a dystrophy and die after is a and about in the past a major has been into to the Various approaches to dystrophin in skeletal muscle by myoblast or gene V. Campbell K.P. Genet. 2000; 9: PubMed Scopus Google Scholar). The most however, with the up-regulation of a dystrophin which been shown to in mice for the of dystrophin Davies Cell. Full Text Full Text PDF PubMed Scopus (57) Google Scholar). α7β1 increased in and mice, et al. Kaufman Kaufman S.J. J. Cell Biol. 2001; PubMed Scopus Google Scholar) the that of the subunit in mice muscle as expressed by the percentage of muscle fibers with was in the and the subunit, increased in with upon of the Kaufman Kaufman S.J. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The high of and the view that α7β1 and the complex are receptors but that increased of α7β1 are of muscle function and the work is to this for The in recent that integrins are both for muscle development and muscle function in the adult and not to the has been by muscular caused by in α5β1 and α7β1 integrins, understanding about the is still and several key through which are both integrins to the are associated with the receptors in skeletal The to these will not only the of the but may new to the for approaches of by integrins.