Severe muscular dystrophy in mice that lack dystrophin and α7 integrin

Rooney, Jachinta E.; Welser, Jennifer V.; Dechert, Melissa A.; Flintoff-Dye, Nichole L.; Kaufman, Stephen J.; Burkin, Dean J.

doi:10.1242/jcs.02952

Cited by 136 publications

(147 citation statements)

References 66 publications

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“…Several lines of evidence suggest positive feedback in the regulation of laminin and ␣ 7 -integrin expression (6,13,15). To test the hypothesis that laminin regulates ␣ 7 -integrin expression, ␣ 7 ␤gal ϩ/Ϫ myoblasts were exposed to 0-200 nM laminin-111 for 24 h. The activity of the ␣ 7 -integrin promoter was measured by ␤-galactosidase cleavage of the nonfluorescent compound fluorescein di-␤-D-galactopyranoside (FDG) to fluorescein.…”

Section: Resultsmentioning

confidence: 99%

“…Transgenic overexpression of the ␣ 7 -integrin in the skeletal muscle of severely dystrophic mice improves muscle pathology and increases lifespan (11). Conversely, loss of the ␣ 7 -integrin in mdx mice results in a more severe dystrophic phenotype and reduced viability, with mice dying prematurely by 4 weeks of age (12,13). Together, these results support the hypothesis that the ␣ 7 ␤ 1 -integrin is a major modifier of muscle disease progression, and drug-based therapies that boost its expression could alleviate DMD.…”

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confidence: 99%

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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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118

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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Section: Resultsmentioning

confidence: 99%

mentioning

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.

Self Cite

118

109

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“…In the integrin a7-deficient mice, the myotendinous junction, the primary site of force transmission between the muscle and the tendon, was severely disrupted, indicating an important role of integrin a7 in the organization and/or maintenance of the myotendinous junction (Mayer et al 1997;Nawrotzki et al 2003). The generation of integrin a7/dystrophin-or integrin a7/ sarcoglycan-double mutant mice demonstrates an essential role for integrin a7 in the maintenance of the DGC-deficient muscle plasma membrane (Allikian et al 2004;Guo et al 2006;Rooney et al 2006). Overexpression of integrin a7 in dystrophin/utrophin double mutant mice, a mouse model for DMD, ameliorates the muscle disease phenotype (Burkin et al 2001).…”

Section: Extracellular Matrix Proteins and Receptorsmentioning

confidence: 98%

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

2006

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Muscular dystrophies are a heterogeneous group of genetic disorders. In addition to genetic information, a combination of various approaches such as the use of genetic animal models, muscle cell biology, and biochemistry has contributed to improving the understanding of the molecular basis of muscular dystrophy's etiology. Several lines of evidence confirm that the structural linkage between the muscle extracellular matrix and the cytoskeleton is crucial to prevent the progression of muscular dystrophy. The dystrophin-glycoprotein complex links the extracellular matrix to the cytoskeleton, and mutations in the component of this complex cause Duchenne-type or limb-girdle-type muscular dystrophy. Mutations in laminin or collagen VI, muscle matrix proteins, are known to cause a congenital type of muscular dystrophy. Moreover, it is not only the primary genetic defects in the structural or matrix proteins, but also the primary mutations of enzymes involved in the protein glycosylation pathway that are now recognized to disrupt the matrix-cell interaction in a certain group of muscular dystrophies. This group of diseases is caused by the secondary functional defects of dystroglycan, a transmembrane matrix receptor. This review considers recent advances in understanding the molecular pathogenesis of muscular dystrophies that can be caused by the disruption of the cell-matrix linkage.

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“…4A). Recent studies [27][28][29] indicate that the DGC and the laminin-binding α7β1 integrin perform overlapping functions in skeletal muscle. However, western blot analysis demonstrated that γ cyto -actin was not altered in dystrophic α7 integrin null muscle compared to control (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cytoplasmic γ-actin expression in diverse animal models of muscular dystrophy

Hanft

Bogan

Mayer

et al. 2007

Neuromuscular Disorders

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We recently showed that cytoplasmic γ-actin (γ cyto -actin) is dramatically elevated in striated muscle of dystrophin-deficient mdx mice. Here we demonstrate that γ cyto -actin is markedly increased in golden retriever muscular dystrophy (GRMD), which better recapitulates the dystrophinopathy phenotype in humans. γ cyto -Actin was also elevated in muscle from α-sarcoglycan null mice, but not in several other dystrophic animal models, including mice deficient in β-sarcoglycan, α-dystrobrevin, laminin-2, or α7 integrin. Muscle from mice lacking dystrophin and utrophin also expressed elevated γ cyto -actin, which was not restored to normal by transgenic overexpression of α7 integrin. However, γ cyto -actin was further elevated in skeletal muscle from GRMD animals treated with the glucocorticoid prednisone at doses shown to improve the dystrophic phenotype and muscle function. These data suggest that elevated γ cyto -actin is part of a compensatory cytoskeletal remodeling program that may partially stabilize dystrophic muscle in some cases where the dystrophinglycoprotein complex is compromised.

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Severe muscular dystrophy in mice that lack dystrophin and α7 integrin

Cited by 136 publications

References 66 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

The genetic and molecular basis of muscular dystrophy: roles of cell–matrix linkage in the pathogenesis

Cytoplasmic γ-actin expression in diverse animal models of muscular dystrophy

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