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Basal lamina strengthens cell membrane integrity via the laminin G domain-binding motif of α-dystroglycan

2009; National Academy of Sciences; Volume: 106; Issue: 31 Linguagem: Inglês

10.1073/pnas.0906545106

1091-6490

Renzhi Han, Motoi Kanagawa, Takako Yoshida‐Moriguchi, Erik P. Rader, Rainer A. Ng, Daniel E. Michele, David Muirhead, Stefan Kunz, Steven A. Moore, Susan T. Iannaccone, Katsuya Miyake, Paul L. McNeil, Ulríke Mayer, Michael B. A. Oldstone, John A. Faulkner, Kevin P. Campbell,

Virus-based gene therapy research

Skeletal muscle basal lamina is linked to the sarcolemma through transmembrane receptors, including integrins and dystroglycan. The function of dystroglycan relies critically on posttranslational glycosylation, a common target shared by a genetically heterogeneous group of muscular dystrophies characterized by alpha-dystroglycan hypoglycosylation. Here we show that both dystroglycan and integrin alpha7 contribute to force-production of muscles, but that only disruption of dystroglycan causes detachment of the basal lamina from the sarcolemma and renders muscle prone to contraction-induced injury. These phenotypes of dystroglycan-null muscles are recapitulated by Large(myd) muscles, which have an intact dystrophin-glycoprotein complex and lack only the laminin globular domain-binding motif on alpha-dystroglycan. Compromised sarcolemmal integrity is directly shown in Large(myd) muscles and similarly in normal muscles when arenaviruses compete with matrix proteins for binding alpha-dystroglycan. These data provide direct mechanistic insight into how the dystroglycan-linked basal lamina contributes to the maintenance of sarcolemmal integrity and protects muscles from damage.