Parallel increasing of α7 and β1 integrin prevents muscular dystrophy in mdx mice

Abstract

Duchenne muscular dystrophy is a devastating muscle disease that is ultimately lethal. Without the dystrophin complex that normally connects myofibers actin cytoskeleton to the laminin in extracellular matrix, membrane integrity of muscle fibers is greatly compromised. One potential therapeutic treatment for muscular dystrophy is to augment the transmembrane linkages by increasing other laminin receptors such as integrins. We previously showed that transgenic expression of α7 chain of the integrin in skeletal muscle effectively alleviates the dystrophic pathologies and extends the lifespan of mdx/utrn−/− mice. However, expression of α7 chain alone in mdx mice provided little improvement of skeletal muscle health. We now found that in transgenic mice expressing high levels of α7 chain, relatively little α7 was targeted to the muscle membrane and thus mostly remained within myofibers, likely due to limiting amount of the endogenous integrin β1 protein. We then demonstrated that overexpress β1D integrin results in α7 chain increase in wild type mice and that commensurate increase of β1 chains in α7 transgenic mice promotes more functional heterodimers targeting to the sarcolemma. Likewise, increasing the amount of β1D integrin in α7-mdx transgenic mice also promotes localization of the α7β1 integrin to the sarcolemma and protects against muscle damages caused by the muscular dystrophy. Our results suggest that parallel increases of α and β integrin subunits are essential to achieve maximal beneficial effects of integrin based therapies for muscular dystrophy. Supported by NIH, MDA & AHA. Grant Funding Source: NIH, MDA, and AHA