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Overexpression of mini‐agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin‐α2‐deficient mice
Author(s) -
Florian Bentzinger C.,
Barzaghi Patrizia,
Lin Shuo,
Ruegg Markus A.
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3376com
Subject(s) - agrin , laminin , basal lamina , congenital muscular dystrophy , skeletal muscle , biology , medicine , endocrinology , muscular dystrophy , microbiology and biotechnology , chemistry , cancer research , anatomy , receptor , extracellular matrix , acetylcholine receptor , ultrastructure
Mutations in the gene encoding the α2 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‐α2, suggesting that the observed amelioration might be due to mini‐agrin's presenting the residual laminin‐α2 to its receptors. Here we show that the mini‐agrin counteracts the disease in dy 3K /dy 3K mice, which are null for laminin‐α2. 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 K /dy K 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‐α2. 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‐α2‐deficient mice. FASEB J. 19, 934–942 (2005)