title: Overexpression of mini-agrin in skeletal muscle increases muscle integrity and regenerative capacity in laminin-alpha2-deficient mice.
abstract: Mutations in the gene encoding the alpha2 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-alpha2, suggesting that the observed amelioration might be due to mini-agrin's presenting the residual laminin-alpha2 to its receptors. Here we show that the mini-agrin counteracts the disease in dy(3K)/dy(3K) mice, which are null for laminin-alpha2. 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-alpha2.
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: C Florian
authors.initials: CF
authors.lastname: Bentzinger
authors.forename: Patrizia
authors.initials: P
authors.lastname: Barzaghi
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: Markus A
authors.initials: MA
authors.lastname: Ruegg
mesh_terms: D018171:Agrin / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001485:Basement Membrane / Q000503:physiopathology / Q000648:ultrastructure; D049030:Dystroglycans / Q000032:analysis; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007797:Laminin / Q000032:analysis / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000737:chemistry / Q000503:physiopathology* / Q000648:ultrastructure; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012508:Sarcolemma / Q000502:physiology / Q000648:ultrastructure
chemical_list: D018171:Agrin; D007797:Laminin; C102645:laminin alpha 2; C097043:laminin alpha5; C507258:miniagrin protein, mouse; D049030:Dystroglycans