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J Clin Invest. Oct 1, 1997; 100(7): 1870–1881.
PMCID: PMC508374

Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy.


Mutations in genes coding for dystrophin, for alpha, beta, gamma, and delta-sarcoglycans, or for the alpha2 chain of the basement membrane component merosin (laminin-2/4) cause various forms of muscular dystrophy. Analyses of integrins showed an abnormal expression and localization of alpha7beta1 isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-deficient humans and animals. It was shown previously that skeletal muscle fibers require merosin for survival and function (Vachon, P.H., F. Loechel, H. Xu, U.M. Wewer, and E. Engvall. 1996. J. Cell Biol. 134:1483-1497). Correction of merosin deficiency in vitro through cell transfection with the merosin alpha2 chain restored the normal localization of alpha7beta1D integrins as well as myotube survival. Overexpression of the apoptosis-suppressing molecule Bcl-2 also promoted the survival of merosin-deficient myotubes, but did not restore a normal expression of alpha7beta1D integrins. Blocking of beta1 integrins in normal myotubes induced apoptosis and severely reduced their survival. These findings (a) identify alpha7beta1D integrins as the de facto receptors for merosin in skeletal muscle; (b) indicate a merosin dependence for the accurate expression and membrane localization of alpha7beta1D integrins in myofibers; (c) provide a molecular basis for the critical role of merosin in myofiber survival; and (d) add new insights to the pathogenesis of neuromuscular disorders.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Mayne R, Sanderson RD. The extracellular matrix of skeletal muscle. Coll Relat Res. 1985 Nov;5(5):449–468. [PubMed]
  • Campbell KP. Three muscular dystrophies: loss of cytoskeleton-extracellular matrix linkage. Cell. 1995 Mar 10;80(5):675–679. [PubMed]
  • Campbell KP, Crosbie RH. Muscular dystrophy. Utrophin to the rescue. Nature. 1996 Nov 28;384(6607):308–309. [PubMed]
  • Wewer UM, Engvall E. Merosin/laminin-2 and muscular dystrophy. Neuromuscul Disord. 1996 Dec;6(6):409–418. [PubMed]
  • Tinsley JM, Blake DJ, Zuellig RA, Davies KE. Increasing complexity of the dystrophin-associated protein complex. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8307–8313. [PMC free article] [PubMed]
  • Mizuno Y, Noguchi S, Yamamoto H, Yoshida M, Nonaka I, Hirai S, Ozawa E. Sarcoglycan complex is selectively lost in dystrophic hamster muscle. Am J Pathol. 1995 Feb;146(2):530–536. [PMC free article] [PubMed]
  • Wewer UM, Engvall E. Laminins. Methods Enzymol. 1994;245:85–104. [PubMed]
  • Engvall E, Wewer UM. Domains of laminin. J Cell Biochem. 1996 Jun 15;61(4):493–501. [PubMed]
  • Leivo I, Engvall E. Merosin, a protein specific for basement membranes of Schwann cells, striated muscle, and trophoblast, is expressed late in nerve and muscle development. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1544–1548. [PMC free article] [PubMed]
  • Helbling-Leclerc A, Zhang X, Topaloglu H, Cruaud C, Tesson F, Weissenbach J, Tomé FM, Schwartz K, Fardeau M, Tryggvason K, et al. Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet. 1995 Oct;11(2):216–218. [PubMed]
  • Hayashi YK, Engvall E, Arikawa-Hirasawa E, Goto K, Koga R, Nonaka I, Sugita H, Arahata K. Abnormal localization of laminin subunits in muscular dystrophies. J Neurol Sci. 1993 Oct;119(1):53–64. [PubMed]
  • Higuchi I, Yamada H, Fukunaga H, Iwaki H, Okubo R, Nakagawa M, Osame M, Roberds SL, Shimizu T, Campbell KP, et al. Abnormal expression of laminin suggests disturbance of sarcolemma-extracellular matrix interaction in Japanese patients with autosomal recessive muscular dystrophy deficient in adhalin. J Clin Invest. 1994 Aug;94(2):601–606. [PMC free article] [PubMed]
  • Wewer UM, Durkin ME, Zhang X, Laursen H, Nielsen NH, Towfighi J, Engvall E, Albrechtsen R. Laminin beta 2 chain and adhalin deficiency in the skeletal muscle of Walker-Warburg syndrome (cerebro-ocular dysplasia-muscular dystrophy). Neurology. 1995 Nov;45(11):2099–2101. [PubMed]
  • Haltia M, Leivo I, Somer H, Pihko H, Paetau A, Kivelä T, Tarkkanen A, Tomé F, Engvall E, Santavuori P. Muscle-eye-brain disease: a neuropathological study. Ann Neurol. 1997 Feb;41(2):173–180. [PubMed]
  • Sunada Y, Bernier SM, Kozak CA, Yamada Y, Campbell KP. Deficiency of merosin in dystrophic dy mice and genetic linkage of laminin M chain gene to dy locus. J Biol Chem. 1994 May 13;269(19):13729–13732. [PubMed]
  • Xu H, Christmas P, Wu XR, Wewer UM, Engvall E. Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5572–5576. [PMC free article] [PubMed]
  • Xu H, Wu XR, Wewer UM, Engvall E. Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene. Nat Genet. 1994 Nov;8(3):297–302. [PubMed]
  • Sunada Y, Bernier SM, Utani A, Yamada Y, Campbell KP. Identification of a novel mutant transcript of laminin alpha 2 chain gene responsible for muscular dystrophy and dysmyelination in dy2J mice. Hum Mol Genet. 1995 Jun;4(6):1055–1061. [PubMed]
  • Minetti C, Bado M, Morreale G, Pedemonte M, Cordone G. Disruption of muscle basal lamina in congenital muscular dystrophy with merosin deficiency. Neurology. 1996 May;46(5):1354–1358. [PubMed]
  • Osari S, Kobayashi O, Yamashita Y, Matsuishi T, Goto M, Tanabe Y, Migita T, Nonaka I. Basement membrane abnormality in merosin-negative congenital muscular dystrophy. Acta Neuropathol. 1996;91(4):332–336. [PubMed]
  • Ishii H, Hayashi YK, Nonaka I, Arahata K. Electron microscopic examination of basal lamina in Fukuyama congenital muscular dystrophy. Neuromuscul Disord. 1997 May;7(3):191–197. [PubMed]
  • Vachon PH, Loechel F, Xu H, Wewer UM, Engvall E. Merosin and laminin in myogenesis; specific requirement for merosin in myotube stability and survival. J Cell Biol. 1996 Sep;134(6):1483–1497. [PMC free article] [PubMed]
  • Ervasti JM, Campbell KP. A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol. 1993 Aug;122(4):809–823. [PMC free article] [PubMed]
  • Cohen MW, Jacobson C, Yurchenco PD, Morris GE, Carbonetto S. Laminin-induced clustering of dystroglycan on embryonic muscle cells: comparison with agrin-induced clustering. J Cell Biol. 1997 Mar 10;136(5):1047–1058. [PMC free article] [PubMed]
  • Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992 Apr 3;69(1):11–25. [PubMed]
  • Ruoslahti E. RGD and other recognition sequences for integrins. Annu Rev Cell Dev Biol. 1996;12:697–715. [PubMed]
  • Lafrenie RM, Yamada KM. Integrin-dependent signal transduction. J Cell Biochem. 1996 Jun 15;61(4):543–553. [PubMed]
  • Ruoslahti E, Reed JC. Anchorage dependence, integrins, and apoptosis. Cell. 1994 May 20;77(4):477–478. [PubMed]
  • Meredith JE, Jr, Schwartz MA. Integrins, adhesion and apoptosis. Trends Cell Biol. 1997 Apr;7(4):146–150. [PubMed]
  • Menko AS, Boettiger D. Occupation of the extracellular matrix receptor, integrin, is a control point for myogenic differentiation. Cell. 1987 Oct 9;51(1):51–57. [PubMed]
  • Volk T, Fessler LI, Fessler JH. A role for integrin in the formation of sarcomeric cytoarchitecture. Cell. 1990 Nov 2;63(3):525–536. [PubMed]
  • Bao ZZ, Lakonishok M, Kaufman S, Horwitz AF. Alpha 7 beta 1 integrin is a component of the myotendinous junction on skeletal muscle. J Cell Sci. 1993 Oct;106(Pt 2):579–589. [PubMed]
  • McDonald KA, Lakonishok M, Horwitz AF. Alpha v and alpha 3 integrin subunits are associated with myofibrils during myofibrillogenesis. J Cell Sci. 1995 Mar;108(Pt 3):975–983. [PubMed]
  • Gettner SN, Kenyon C, Reichardt LF. Characterization of beta pat-3 heterodimers, a family of essential integrin receptors in C. elegans. J Cell Biol. 1995 May;129(4):1127–1141. [PMC free article] [PubMed]
  • Sastry SK, Lakonishok M, Thomas DA, Muschler J, Horwitz AF. Integrin alpha subunit ratios, cytoplasmic domains, and growth factor synergy regulate muscle proliferation and differentiation. J Cell Biol. 1996 Apr;133(1):169–184. [PMC free article] [PubMed]
  • George-Weinstein M, Foster RF, Gerhart JV, Kaufman SJ. In vitro and in vivo expression of alpha 7 integrin and desmin define the primary and secondary myogenic lineages. Dev Biol. 1993 Mar;156(1):209–229. [PubMed]
  • Echtermeyer F, Schöber S, Pöschl E, von der Mark H, von der Mark K. Specific induction of cell motility on laminin by alpha 7 integrin. J Biol Chem. 1996 Jan 26;271(4):2071–2075. [PubMed]
  • Yao CC, Ziober BL, Sutherland AE, Mendrick DL, Kramer RH. Laminins promote the locomotion of skeletal myoblasts via the alpha 7 integrin receptor. J Cell Sci. 1996 Dec;109(Pt 13):3139–3150. [PubMed]
  • Collo G, Starr L, Quaranta V. A new isoform of the laminin receptor integrin alpha 7 beta 1 is developmentally regulated in skeletal muscle. J Biol Chem. 1993 Sep 5;268(25):19019–19024. [PubMed]
  • Song WK, Wang W, Sato H, Bielser DA, Kaufman SJ. Expression of alpha 7 integrin cytoplasmic domains during skeletal muscle development: alternate forms, conformational change, and homologies with serine/threonine kinases and tyrosine phosphatases. J Cell Sci. 1993 Dec;106(Pt 4):1139–1152. [PubMed]
  • Belkin AM, Zhidkova NI, Balzac F, Altruda F, Tomatis D, Maier A, Tarone G, Koteliansky VE, Burridge K. Beta 1D integrin displaces the beta 1A isoform in striated muscles: localization at junctional structures and signaling potential in nonmuscle cells. J Cell Biol. 1996 Jan;132(1-2):211–226. [PMC free article] [PubMed]
  • Martin PT, Kaufman SJ, Kramer RH, Sanes JR. Synaptic integrins in developing, adult, and mutant muscle: selective association of alpha1, alpha7A, and alpha7B integrins with the neuromuscular junction. Dev Biol. 1996 Feb 25;174(1):125–139. [PubMed]
  • Sewry CA, Chevallay M, Tomé FM. Expression of laminin subunits in human fetal skeletal muscle. Histochem J. 1995 Jul;27(7):497–504. [PubMed]
  • Schuler F, Sorokin LM. Expression of laminin isoforms in mouse myogenic cells in vitro and in vivo. J Cell Sci. 1995 Dec;108(Pt 12):3795–3805. [PubMed]
  • Kroll TG, Peters BP, Hustad CM, Jones PA, Killen PD, Ruddon RW. Expression of laminin chains during myogenic differentiation. J Biol Chem. 1994 Mar 25;269(12):9270–9277. [PubMed]
  • Argraves WS, Suzuki S, Arai H, Thompson K, Pierschbacher MD, Ruoslahti E. Amino acid sequence of the human fibronectin receptor. J Cell Biol. 1987 Sep;105(3):1183–1190. [PMC free article] [PubMed]
  • Balzac F, Belkin AM, Koteliansky VE, Balabanov YV, Altruda F, Silengo L, Tarone G. Expression and functional analysis of a cytoplasmic domain variant of the beta 1 integrin subunit. J Cell Biol. 1993 Apr;121(1):171–178. [PMC free article] [PubMed]
  • Languino LR, Ruoslahti E. An alternative form of the integrin beta 1 subunit with a variant cytoplasmic domain. J Biol Chem. 1992 Apr 5;267(10):7116–7120. [PubMed]
  • Liu L, Vachon PH, Kuang W, Xu H, Wewer UM, Kylsten P, Engvall E. Mouse adhalin: primary structure and expression during late stages of muscle differentiation in vitro. Biochem Biophys Res Commun. 1997 Jun 9;235(1):227–235. [PubMed]
  • Ibraghimov-Beskrovnaya O, Milatovich A, Ozcelik T, Yang B, Koepnick K, Francke U, Campbell KP. Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization. Hum Mol Genet. 1993 Oct;2(10):1651–1657. [PubMed]
  • Giancotti FG, Stepp MA, Suzuki S, Engvall E, Ruoslahti E. Proteolytic processing of endogenous and recombinant beta 4 integrin subunit. J Cell Biol. 1992 Aug;118(4):951–959. [PMC free article] [PubMed]
  • Ehrig K, Leivo I, Argraves WS, Ruoslahti E, Engvall E. Merosin, a tissue-specific basement membrane protein, is a laminin-like protein. Proc Natl Acad Sci U S A. 1990 May;87(9):3264–3268. [PMC free article] [PubMed]
  • Haaparanta T, Uitto J, Ruoslahti E, Engvall E. Molecular cloning of the cDNA encoding human laminin A chain. Matrix. 1991 Jun;11(3):151–160. [PubMed]
  • Hanada M, Aimé-Sempé C, Sato T, Reed JC. Structure-function analysis of Bcl-2 protein. Identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J Biol Chem. 1995 May 19;270(20):11962–11969. [PubMed]
  • Giancotti FG, Ruoslahti E. Elevated levels of the alpha 5 beta 1 fibronectin receptor suppress the transformed phenotype of Chinese hamster ovary cells. Cell. 1990 Mar 9;60(5):849–859. [PubMed]
  • Zhang Z, Vuori K, Reed JC, Ruoslahti E. The alpha 5 beta 1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci U S A. 1995 Jun 20;92(13):6161–6165. [PMC free article] [PubMed]
  • Kühl U, Timpl R, von der Mark K. Synthesis of type IV collagen and laminin in cultures of skeletal muscle cells and their assembly on the surface of myotubes. Dev Biol. 1982 Oct;93(2):344–354. [PubMed]
  • Meredith JE, Jr, Fazeli B, Schwartz MA. The extracellular matrix as a cell survival factor. Mol Biol Cell. 1993 Sep;4(9):953–961. [PMC free article] [PubMed]
  • Boudreau N, Sympson CJ, Werb Z, Bissell MJ. Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science. 1995 Feb 10;267(5199):891–893. [PMC free article] [PubMed]
  • Pullan S, Wilson J, Metcalfe A, Edwards GM, Goberdhan N, Tilly J, Hickman JA, Dive C, Streuli CH. Requirement of basement membrane for the suppression of programmed cell death in mammary epithelium. J Cell Sci. 1996 Mar;109(Pt 3):631–642. [PubMed]
  • Frisch SM, Vuori K, Kelaita D, Sicks S. A role for Jun-N-terminal kinase in anoikis; suppression by bcl-2 and crmA. J Cell Biol. 1996 Dec;135(5):1377–1382. [PMC free article] [PubMed]
  • Gajewski TF, Thompson CB. Apoptosis meets signal transduction: elimination of a BAD influence. Cell. 1996 Nov 15;87(4):589–592. [PubMed]
  • Dowling J, Yu QC, Fuchs E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol. 1996 Jul;134(2):559–572. [PMC free article] [PubMed]
  • Georges-Labouesse E, Messaddeq N, Yehia G, Cadalbert L, Dierich A, Le Meur M. Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet. 1996 Jul;13(3):370–373. [PubMed]
  • van der Neut R, Krimpenfort P, Calafat J, Niessen CM, Sonnenberg A. Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat Genet. 1996 Jul;13(3):366–369. [PubMed]
  • Matsuda R, Nishikawa A, Tanaka H. Visualization of dystrophic muscle fibers in mdx mouse by vital staining with Evans blue: evidence of apoptosis in dystrophin-deficient muscle. J Biochem. 1995 Nov;118(5):959–964. [PubMed]
  • Tidball JG, Albrecht DE, Lokensgard BE, Spencer MJ. Apoptosis precedes necrosis of dystrophin-deficient muscle. J Cell Sci. 1995 Jun;108(Pt 6):2197–2204. [PubMed]
  • Dalton SL, Scharf E, Briesewitz R, Marcantonio EE, Assoian RK. Cell adhesion to extracellular matrix regulates the life cycle of integrins. Mol Biol Cell. 1995 Dec;6(12):1781–1791. [PMC free article] [PubMed]
  • Delcommenne M, Streuli CH. Control of integrin expression by extracellular matrix. J Biol Chem. 1995 Nov 10;270(45):26794–26801. [PubMed]
  • DiPersio CM, Shah S, Hynes RO. alpha 3A beta 1 integrin localizes to focal contacts in response to diverse extracellular matrix proteins. J Cell Sci. 1995 Jun;108(Pt 6):2321–2336. [PubMed]
  • Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol. 1995 Nov;131(3):791–805. [PMC free article] [PubMed]
  • Martin-Bermudo MD, Brown NH. Intracellular signals direct integrin localization to sites of function in embryonic muscles. J Cell Biol. 1996 Jul;134(1):217–226. [PMC free article] [PubMed]
  • Durkin ME, Gautam M, Loechel F, Sanes JR, Merlie JP, Albrechtsen R, Wewer UM. Structural organization of the human and mouse laminin beta2 chain genes, and alternative splicing at the 5' end of the human transcript. J Biol Chem. 1996 Jun 7;271(23):13407–13416. [PubMed]
  • Martin PT, Ettinger AJ, Sanes JR. A synaptic localization domain in the synaptic cleft protein laminin beta 2 (s-laminin) Science. 1995 Jul 21;269(5222):413–416. [PubMed]
  • Wewer UM, Thornell LE, Loechel F, Zhang X, Durkin ME, Amano S, Burgeson RE, Engvall E, Albrechtsen R, Virtanen I. Extrasynaptic location of laminin beta 2 chain in developing and adult human skeletal muscle. Am J Pathol. 1997 Aug;151(2):621–631. [PMC free article] [PubMed]
  • Miner JH, Patton BL, Lentz SI, Gilbert DJ, Snider WD, Jenkins NA, Copeland NG, Sanes JR. The laminin alpha chains: expression, developmental transitions, and chromosomal locations of alpha1-5, identification of heterotrimeric laminins 8-11, and cloning of a novel alpha3 isoform. J Cell Biol. 1997 May 5;137(3):685–701. [PMC free article] [PubMed]
  • Hynes RO. Targeted mutations in cell adhesion genes: what have we learned from them? Dev Biol. 1996 Dec 15;180(2):402–412. [PubMed]
  • DiPersio CM, Hodivala-Dilke KM, Jaenisch R, Kreidberg JA, Hynes RO. alpha3beta1 Integrin is required for normal development of the epidermal basement membrane. J Cell Biol. 1997 May 5;137(3):729–742. [PMC free article] [PubMed]

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