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Overexpression of mini-agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin-2-deficient mice

Biozentrum, University of Basel, Basel, Switzerland

¹Correspondence: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. E-mail: markus-a.ruegg{at}unibas.ch

Mutations in the gene encoding the 2 subunit of laminins cause the severe "merosin-deficient congenital muscular dystrophy" (MDC1A). We have recently shown that overexpression of a miniaturized form of the molecule agrin (mini-agrin) counteracts the disease in dy^W/dy^W mice, a model for MDC1A. However, these mice express some residual truncated laminin-2, suggesting that the observed amelioration might be due to mini-agrin’s presenting the residual laminin-2 to its receptors. Here we show that the mini-agrin counteracts the disease in dy^3K/dy^3K mice, which are null for laminin-2. As in dy^W/dy^W mice, mini-agrin improves both the function and structure of muscle. We show that muscle regeneration after injury is severely impaired in dy^3K/dy^3K mice but is restored in the mini-agrin-expressing littermates. In summary, our results 1) show that the direct linkage of muscle basal lamina with the sarcolemma is the basis of mini-agrin-mediated amelioration and 2) provide unprecedented evidence that this linkage is important for proper regeneration of muscle fibers after injury. Our findings thus suggest that treatment with mini-agrin might be beneficial over the entire spectrum of the MDC1A disease, whose severity inversely correlates with expression levels and the size of the truncation in laminin-2.—Bentzinger, C. F., Barzaghi, P., Lin, S., Ruegg, M. A., Overexpression of mini-agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin-2-deficient mice.

Key Words: muscular dystrophy • laminin-2 deficiency • muscle regeneration

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