Enhanced Expression of the α7β1 Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice

Abstract

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the α7β1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), α2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and α7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the α7β1 integrin can compensate for the absence of dystrophin, we expressed the rat α7 chain in mdx/utr−/− mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the α7BX2 integrin chain was increased 2.0–2.3-fold in mdx/utr−/− mice. Concomitant with the increase in the α7 chain, its heterodimeric partner, β1D, was also increased in the transgenic animals. Transgenic expression of the α7BX2 chain in the mdx/utr−/− mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering α7β1 integrin–mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr−/− mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the α7β1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr−/− and α7BX2-mdx/utr−/−mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth or neuromuscular development: Evidence for a utrophin-independent mechanism

“…In addition, CT-glycosylated proteins where protein turnover has been stimulated or where protein secretion has occurred may not be evident in this type of assay. The lack of upregulation of integrin α7B, another molecule that can ameliorate aspects of muscular dystrophy in mdx utrn-/-muscles [38], also points to the novelty of the effect with Galgt2. Indeed, Galgt2 overexpression is the only therapy shown to inhibit the development of muscle pathology in mdx utrn-/-muscles, which again sets it apart from integrin α7B [38].…”

“…The lack of upregulation of integrin α7B, another molecule that can ameliorate aspects of muscular dystrophy in mdx utrn-/-muscles [38], also points to the novelty of the effect with Galgt2. Indeed, Galgt2 overexpression is the only therapy shown to inhibit the development of muscle pathology in mdx utrn-/-muscles, which again sets it apart from integrin α7B [38]. The demonstration that Galgt2 does not require utrophin to be therapeutic suggests it should be considered as a distinct target for therapeutic intervention in DMD.…”

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

“…Because dystrophy persists, these parallel linkages are either not completely redundant with the DGC, or the compensatory upregulation/recruitment is not maximal. In support of the latter possibility, transgenic overexpression of α7 integrin has been shown to partially compensate for the combined deficiency of dystrophin and utrophin [12].…”

“…4B). Finally, mice deficient in both dystrophin and utrophin (mdx/utrn −/−) present with a more severe DMD-like phenotype [30,31], which is partially rescued by transgenic overexpression of α7 integrin [12]. Therefore, we examined how the combined absence of dystrophin and utrophin as well as α7 integrin overexpression affected γ cyto -actin protein levels.…”

“…Mice deficient for α-sarcoglycan, β-sarcoglycan, α-dystrobrevin or α7 integrin were described previously [8][9][10][11] and were analyzed at 14-16 weeks of age. Transgenic mice overexpressing α7 integrin [12] were bred onto mdx, and mdx/utrophin −/− double knockout (mdx/utrn−/−) backgrounds and analyzed at 6 weeks of age. Muscle biopsies from control and GRMD dogs were described previously [7].…”