α<sub>7</sub>β<sub>1</sub>-Integrin regulates mechanotransduction and prevents skeletal muscle injury

Boppart, Marni D.; Burkin, Dean J.; Kaufman, Stephen J.

doi:10.1152/ajpcell.00317.2005

Cited by 117 publications

(131 citation statements)

References 45 publications

(58 reference statements)

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“…Several genes have been shown to compensate for the loss of dystrophin and rescue dystrophic mice, including ␣ 7 ␤ 1 -integrin (11,18). Studies demonstrate that ␣ 7 ␤ 1 -integrin contributes to the structural and functional integrity of skeletal muscle (18)(19)(20). Because ␣ 7 ␤ 1 -integrin is expressed ubiquitously in skeletal and cardiac muscles, small molecule-based or protein-based approaches that target the expression of this gene hold significant promise for the treatment of DMD.…”

Section: Discussionmentioning

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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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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Section: Discussionmentioning

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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“…Protocols for animal use were approved by the Institutional Animal Care and Use Committee, University of Illinois at Urbana-Champaign. The ␣ 7-integrin transgenic mice used in this study were previously described (7). Weights of 30 animals of each sex were measured weekly for up to 30 wk.…”

Section: Methodsmentioning

confidence: 99%

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Liu

Burkin²,

Kaufman

2008

American Journal of Physiology-Cell Physiology

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Liu J, Burkin DJ, Kaufman SJ. Increasing ␣7␤1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression. Am J Physiol Cell Physiol 294: C627-C640, 2008. First published November 28, 2007 doi:10.1152/ajpcell.00329.2007.-The dystrophin-glycoprotein complex maintains the integrity of skeletal muscle by associating laminin in the extracellular matrix with the actin cytoskeleton. Several human muscular dystrophies arise from defects in the components of this complex. The ␣ 7␤1-integrin also binds laminin and links the extracellular matrix with the cytoskeleton. Enhancement of ␣ 7-integrin levels alleviates pathology in mdx/utrn Ϫ/Ϫ mice, a model of Duchenne muscular dystrophy, and thus the integrin may functionally compensate for the absence of dystrophin. To test whether increasing ␣ 7-integrin levels affects transcription and cellular functions, we generated ␣ 7-integrin-inducible C2C12 cells and transgenic mice that overexpress the integrin in skeletal muscle. C2C12 myoblasts with elevated levels of integrin exhibited increased adhesion to laminin, faster proliferation when serum was limited, resistance to staurosporine-induced apoptosis, and normal differentiation. Transgenic expression of eightfold more integrin in skeletal muscle did not result in notable toxic effects in vivo. Moreover, high levels of ␣ 7-integrin in both myoblasts and in skeletal muscle did not disrupt global gene expression profiles. Thus increasing integrin levels can compensate for defects in the extracellular matrix and cytoskeleton linkage caused by compromises in the dystrophin-glycoprotein complex without triggering apparent overt negative side effects. These results support the use of integrin enhancement as a therapy for muscular dystrophy. myoblast proliferation; integrin transgenic mice; microarray CELLS CAN RECOGNIZE AND INTERACT with their environment through membrane receptors specific for different extracellular matrix proteins. The heterodimeric integrins are evolutionarily conserved receptors for matrix proteins found in all metazoans (37). In skeletal muscle, the association of the extracellular matrix with the cytoskeleton is essential for maintaining the integrity of the sarcolemma, sustaining appropriate myofiber architecture, and correctly transmitting the forces produced by muscle contractions (5, 42). The ␣ 7 ␤ 1 -integrin is part of a linkage system that maintains such transmembrane associations in skeletal muscle (10,66). It binds to laminin in the basal lamina that surrounds muscle fibers. Within muscle fibers, the integrin associates with the subsarcolemmal cytoskeleton network through focal adhesion complexes (5). The ␣ 7 ␤ 1 -integrin is distributed along the sarcolemma at costameres, and it is also concentrated at neuromuscular and myotendinous junctions (2,48). This localization suggests that the integrin has a pivotal role in maintaining these specialized structures and their functions in skeletal muscle. Congenital myopathies caused by mutations in t...

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“…330). This physical tethering is critical for satellite cell activation as it allows the transduction of extracellular mechanical force into intracellular chemical signals (62;reviewed in Ref. 73).…”

Section: Ecm and Associated Factorsmentioning

confidence: 99%

Satellite Cells and the Muscle Stem Cell Niche

Yin

Price

Rudnicki

2013

Physiological Reviews

1,715

1,808

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LYin H, Price F, Rudnicki MA. Satellite Cells and the Muscle Stem Cell Niche. Physiol Rev 93: 23-67, 2013; doi:10.1152/physrev.00043.2011.-Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process involving the activation of various cellular and molecular responses. As skeletal muscle stem cells, satellite cells play an indispensible role in this process. The self-renewing proliferation of satellite cells not only maintains the stem cell population but also provides numerous myogenic cells, which proliferate, differentiate, fuse, and lead to new myofiber formation and reconstitution of a functional contractile apparatus. The complex behavior of satellite cells during skeletal muscle regeneration is tightly regulated through the dynamic interplay between intrinsic factors within satellite cells and extrinsic factors constituting the muscle stem cell niche/microenvironment. For the last half century, the advance of molecular biology, cell biology, and genetics has greatly improved our understanding of skeletal muscle biology. Here, we review some recent advances, with focuses on functions of satellite cells and their niche during the process of skeletal muscle regeneration.

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α₇β₁-Integrin regulates mechanotransduction and prevents skeletal muscle injury

Cited by 117 publications

References 45 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

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Satellite Cells and the Muscle Stem Cell Niche

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α7β1-Integrin regulates mechanotransduction and prevents skeletal muscle injury

Cited by 117 publications

References 45 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

Increasing α7β1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression

Satellite Cells and the Muscle Stem Cell Niche

Contact Info

Product

Resources

About

α₇β₁-Integrin regulates mechanotransduction and prevents skeletal muscle injury

Increasing α₇β₁-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression