Abstract
The dystrophin-associated glycoprotein complex (DGC) is found at the muscle fiber sarcolemma and forms an essential structural link between the basal lamina and internal cytoskeleton. In a set of muscular dystrophies known as the dystroglycanopathies, hypoglycosylation of the DGC component α-dystroglycan results in reduced binding to basal lamina components, a loss in structural stability, and repeated cycles of muscle fiber degeneration and regeneration. The satellite cells are the key stem cells responsible for muscle repair and reside between the basal lamina and sarcolemma. In this study, we aimed to determine whether pathological changes associated with the dystroglycanopathies affect satellite cell function. In the Largemyd mouse dystroglycanopathy model, satellite cells are present in significantly greater numbers but display reduced proliferation on their native muscle fibers in vitro, compared with wild type. However, when removed from their fiber, proliferation in culture is restored to that of wild type. Immunohistochemical analysis of Largemyd muscle reveals alterations to the basal lamina and interstitium, including marked disorganization of laminin, upregulation of fibronectin and collagens. Proliferation and differentiation of wild-type satellite cells is impaired when cultured on substrates such as collagen and fibronectin, compared with laminins. When engrafted into irradiated tibialis anterior muscles of mdx-nude mice, wild-type satellite cells expanded on laminin contribute significantly more to muscle regeneration than those expanded on fibronectin. These results suggest that defects in α-dystroglycan glycosylation are associated with an alteration in the satellite cell niche, and that regenerative potential in the dystroglycanopathies may be perturbed.
Highlights
The dystroglycanopathies are a set of muscular dystrophies characterized by defects in the glycosylation of a-dystroglycan, a component of the dystrophin-associated glycoprotein complex [1,2,3]
Apoptosis was very rare in wild-type or Largemyd mice at each of the time points (
We report that satellite cell proliferation is impaired in the LargemydÀ/À mouse, and that this may at least be a partial result of an altered basal lamina microenvironment
Summary
The dystroglycanopathies are a set of muscular dystrophies characterized by defects in the glycosylation of a-dystroglycan, a component of the dystrophin-associated glycoprotein complex [1,2,3] This multiprotein complex is present at the sarcolemma and links the external extracellular matrix (ECM) to the internal actin cytoskeleton of muscle fibers. Among these are the glycosyltransferases that transfer glycan structures onto a-dystroglycan: protein O-mannosyltransferases 1 and 2 (POMT1 and 2) [10]; protein O-linked-mannose b-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) [11], Author contributions: J.R.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; A.B., J.J., and L.B.: collection and/or assembly of data and final approval of manuscript; F.M.: conception and design, financial support, and final approval of manuscript; J.E.H.: conception and design, manuscript writing, and final approval of manuscript; S.C.B. and J.E.M.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript
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