The α7β1 integrin in muscle development and disease

Burkin, Dean J.; Kaufman, Stephen J.

doi:10.1007/s004410051279

Cited by 252 publications

(249 citation statements)

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“…The ␣ 7 ␤ 1 -integrin is the predominant laminin-binding integrin in cardiac and skeletal muscle (7). Mutations in the ␣ 7 -integrin gene cause congenital myopathy in both humans and mice (8)(9)(10).…”

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confidence: 99%

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Rooney¹,

Gurpur²,

Burkin

2009

Proc. Natl. Acad. Sci. U.S.A.

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116

109

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Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α 7 β 1 -integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the mdx mouse model. Transgenic overexpression of the α 7 -integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate α 7 -integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for α 7 -integrin expression. We show that laminin-111 (α 1 , β 1 , γ 1 ), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased α 7 -integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the mdx mouse model of DMD increased expression of α 7 -integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the mdx mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.

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confidence: 99%

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Rooney¹,

Gurpur²,

Burkin

2009

Proc. Natl. Acad. Sci. U.S.A.

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116

109

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“…In mouse, ADAM12 positively modulates expression of integrin ␣ 7 (Cao et al, 2003;Moghadaszadeh et al, 2003), which has functions in skeletal muscle development and disease (Burkin and Kaufman, 1999). ␣ 7 ␤ 1 integrin is mainly involved in mpc adhesion and migration on the matrix component laminin (Yao et al, 1996;Crawley et al, 1997;Blanco-Bose and Blau, 2001) and in myotendinous junction formation (Nawrotzki et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

Lafuste

Sonnet

Chazaud

et al. 2005

MBoC

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Knowledge on molecular systems involved in myogenic precursor cell (mpc) fusion into myotubes is fragmentary. Previous studies have implicated the a disintegrin and metalloproteinase (ADAM) family in most mammalian cell fusion processes. ADAM12 is likely involved in fusion of murine mpc and human rhabdomyosarcoma cells, but it requires yet unknown molecular partners to launch myogenic cell fusion. ADAM12 was shown able to mediate cell-to-cell attachment through binding ␣ 9 ␤ 1 integrin. We report that normal human mpc express both ADAM12 and ␣ 9 ␤ 1 integrin during their differentiation. Expression of ␣ 9 parallels that of ADAM12 and culminates at time of fusion. ␣ 9 and ADAM12 coimmunoprecipitate and participate to mpc adhesion. Inhibition of ADAM12/␣ 9 ␤ 1 integrin interplay, by either ADAM12 antisense oligonucleotides or blocking antibody to ␣ 9 ␤ 1 , inhibited overall mpc fusion by 47-48%, with combination of both strategies increasing inhibition up to 62%. By contrast with blockade of vascular cell adhesion molecule-1/␣ 4 ␤ 1 , which also reduced fusion, exposure to ADAM12 antisense oligonucleotides or anti-␣ 9 ␤ 1 antibody did not induce detachment of mpc from extracellular matrix, suggesting specific involvement of ADAM12-␣ 9 ␤ 1 interaction in the fusion process. Evaluation of the fusion rate with regard to the size of myotubes showed that both ADAM12 antisense oligonucleotides and ␣ 9 ␤ 1 blockade inhibited more importantly formation of large (>5 nuclei) myotubes than that of small (2-4 nuclei) myotubes. We conclude that both ADAM12 and ␣ 9 ␤ 1 integrin are expressed during postnatal human myogenic differentiation and that their interaction is mainly operative in nascent myotube growth. INTRODUCTIONAdult skeletal muscle regeneration after injury results from activation, proliferation, and fusion of mononucleated myogenic precursor cells (mpc) (Hawke and Garry, 2001). The mpc fusion results from an ordered sequence of events, including clustering and alignment of cells, establishment of close cell-to-cell contacts, and plasma membrane merging (Doberstein et al., 1997;Taylor, 2003). Various membrane proteins have been implicated in myotube formation, including N-and M-cadherins, neural cell adhesion molecule (NCAM), and vascular cell adhesion molecule (VCAM), ␣ 4 ␤ 1 and other integrins, and a disintegrin and metalloproteinases (ADAMs) (Abmayr et al., 2003). ADAMs form a family of Ͼ30 transmembrane glycoproteins with a unique domain organization, including a prodomain, a proteolytic domain (metalloprotease), an adhesion integrin-binding site formed by both disintegrin and cysteine-rich domains, an epidermal growth factor-like domain, a transmembrane domain, and a signaling cytoplasmic tail (Huovila et al., 1996;Primakoff and Myles, 2002;White, 2003). In addition, some ADAMs contain a hydrophobic sequence in a cysteine-rich region that may represent a fusion peptide, suggesting that this subclass of ADAMs might participate to plasma membrane merging (Huovila et al., 1996). Some ADAMs have been implicated i...

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“…Therefore, we have established a cell-free screening assay in which we used a recombinantly expressed soluble ␣ 7 ␤ 1 integrin heterodimer and its binding to laminin-1. Within the muscle, ␣ 7 ␤ 1 is highly concentrated at the myotendinous and neuromuscular junctions, which are essential for the transduction of mechanical forces and nerve signals, respectively (12). Because ␣ 7 X2␤ 1 integrin seems to be the only isoform involved in laminininduced acetylcholine receptor recruitment into neuromuscular junctions (12) and is the predominant isoform in adult skeletal muscle, the splice variant X2 was chosen for recombinant production.…”

Section: K Dmentioning

confidence: 99%

“…Within the muscle, ␣ 7 ␤ 1 is highly concentrated at the myotendinous and neuromuscular junctions, which are essential for the transduction of mechanical forces and nerve signals, respectively (12). Because ␣ 7 X2␤ 1 integrin seems to be the only isoform involved in laminininduced acetylcholine receptor recruitment into neuromuscular junctions (12) and is the predominant isoform in adult skeletal muscle, the splice variant X2 was chosen for recombinant production. A high yield expression of soluble ␣ 7 X2␤ 1 integrin was achieved by coexpression of the murine ␣ 7 X2 integrin ectodomain with the human ␤ 1 integrin ectodomain in Drosophila Schneider's cells.…”

Section: K Dmentioning

confidence: 99%

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Vipera lebetina Venom Contains Two Disintegrins Inhibiting Laminin-binding β1 Integrins

Eble

Brückner

Mayer

2003

Journal of Biological Chemistry

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To explain the myotoxic effects of snake venoms, we searched for inhibitors of ␣ 7 ␤ 1 integrin, the major laminin-binding integrin in skeletal muscle. We discovered two inhibitors in the venom of Vipera lebetina. One of them, lebein-1 (known as lebein), has already been proposed to be a disintegrin because of its RGD-containing primary sequence. The other, lebein-2, is a novel protein that also interacts firmly with ␣ 3 ␤ 1 , ␣ 6 ␤ 1 , and ␣ 7 ␤ 1 integrins, but not with the collagen-binding ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins. Ligand binding of laminin-recognizing ␤ 1 integrins was efficiently blocked by both lebein-1 and lebein-2. In cell attachment assays, lebein-1 and lebein-2 inhibited myoblast attachment not only to laminin, but also to fibronectin. However, neither lebein-1 nor lebein-2 interacted with ␣ 7 ␤ 1 integrin in an RGD-dependent manner, similar to the interaction of the laminin with ␣ 7 ␤ 1 integrin. Identical divalent cation dependence of integrin binding to laminin and to either of the two inhibitors and their mutually exclusive binding suggest that both lebein-1 and lebein-2 interact with the ligandbinding site of laminin-binding ␤ 1 integrins by mimicking the yet unknown integrin-binding structure of laminins. Like lebein-1, lebein-2 is a soluble heterodimeric disintegrin of low molecular mass. Together with membrane-bound ADAM-2 and ADAM-9, the two inhibitors seem to form a small group of disintegrins that can bind to laminin-binding ␤ 1 integrins. Because of their inhibitory capability both in vitro and in vivo, lebein-1 and lebein-2 may be valuable tools in influencing laminininduced, integrin-mediated cell functions such as cell anchorage, migration, and mechanical force transduction on laminin-rich basement membranes.

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The α7β1 integrin in muscle development and disease

Cited by 252 publications

References 29 publications

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

Vipera lebetina Venom Contains Two Disintegrins Inhibiting Laminin-binding β1 Integrins

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The α7β1 integrin in muscle development and disease

Cited by 252 publications

References 29 publications

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

Laminin-111 protein therapy prevents muscle disease in the mdx mouse model for Duchenne muscular dystrophy

ADAM12 and α9β1Integrin Are Instrumental in Human Myogenic Cell Differentiation

Vipera lebetina Venom Contains Two Disintegrins Inhibiting Laminin-binding β1 Integrins

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ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation