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Utrophin requires α-Syntrophin to maintain neuromuscular junction integrity in mdx mice
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DOI：10.1093/hmg/ddag060.png)
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Abstract
En 中文
Dystrophin links the actin cytoskeleton to the extracellular matrix through the dystrophin–glycoprotein complex (DGC), providing structural stability to muscle fibers. In mdx mice, which lack dystrophin, neuromuscular junctions (NMJs) remain largely structurally and functionally intact despite extensive muscle pathology. Here, using single- and double-mutant mice deficient in dystrophin and α-syntrophin (α-syn), we investigated how utrophin upregulation contributes to NMJ maintenance in dystrophic muscle. During early postnatal development, when dystrophic muscles are transiently resistant to degeneration, the DGC proteins α-dystrobrevin, α-syn, and β-dystroglycan are broadly distributed along both synaptic and extra-synaptic regions of the sarcolemma, although their overall levels are reduced compared with wild-type (WT) muscle. In contrast, in WT mice, utrophin is restricted to NMJs, whereas in dystrophic muscles from both mutants, it is distributed along both synaptic and extra-synaptic regions of the sarcolemma, particularly within the innervated zone of muscle fibers. As muscles mature and degeneration begins, these DGC components become highly restricted to NMJs while being markedly reduced or absent from the extra-synaptic sarcolemma in many muscle cells. Although utrophin remains highly enriched at synaptic sites in mdx:α-syn−/− muscles, their NMJs display severe structural abnormalities compared with those of mdx mice. These include a dramatic reduction in synaptic fold depth and density, a decrease in presynaptic vesicle density, retraction of nerve terminals, and axonal thinning. These findings demonstrate that utrophin localization at the NMJ is not sufficient to preserve synaptic integrity and that functional interactions between utrophin and α-syn are required to maintain the NMJ in dystrophic muscle.
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