Large-Mediated Glycosylation of Dystroglycan in Skeletal Muscle Function.

[摘要] Dystroglycan is a glycosylation-dependent extracellular matrix receptor implicated in a subset of muscle diseases associated with mutations in known or putative glycosyltransferases.The glycosylation-deficient muscular dystrophies share a common biochemical defect in the glycosylation of dystroglycan and result in a multi-system muscle disease that includes impairments in nerve function and brain architecture.Mutations in the putative glycosyltransferase LARGE cause muscular dystrophy in humans and in the LARGEmyd mouse.Although dystroglycan has essential functions in skeletal muscle, whether impaired glycosylation of dystroglycan is sufficient to explain all complex pathological features associated with LARGE-deficient muscular dystrophy is less clear.A novel transgenic mouse with muscle-specific overexpression of LARGE was generated and used in combination with the LARGEmyd mouse model in order to determine the selective consequence of enhanced or impaired dystroglycan function in skeletal muscle and neuronal tissues.Muscles from LARGEmyd animals were weaker than wild-type littermates but only fast-twitch muscles were susceptible to mechanical injury.Complementary to this result, overexpression of LARGE in normal skeletal muscle resulted in hyperglycosylation and enhanced function of dystroglycan, but only fast-twitch muscle demonstrated enhanced protection from mechanical injury.Furthermore, the identification of differential expression of dystroglycan and α7β1 integrin in fast-twitch versus slow-twitch muscle suggests that the two receptors may have fiber-type specific functions.Overexpression of LARGE in LARGEmyd animals resulted in complete amelioration of muscle disease as evidenced by an absence of muscle pathology and a restoration of contractile function.While deficits in neuromuscular transmission were observed in LARGEmyd animals, these deficits were fully rescued by expression of LARGE in muscle fibers in parallel with restoration of neuromuscular junction structure.This suggests that neurotransmission contributes to muscle weakness in LARGEmyd mice and that impaired neurotransmission can be restored via expression of LARGE exclusively in skeletal muscle.These results provide evidence for critical functions of LARGE-mediated glycosylation at both the lateral membrane and at the neuromuscular junction of skeletal muscle fibers and demonstrate that neuronal deficits associated with impaired dystroglycan function may be exacerbated by impaired muscle function and/or communication at the neuromuscular junction.

[发布机构] University of Michigan

[效力级别] DGC

[关键词] Dystroglycan;DGC;Glycosyltransferase;Muscle;Physiology;Science;Molecular and Integrative Physiology