Neuromuscular synapse integrity requires linkage of acetylcholine receptors to postsynaptic intermediate filament networks via rapsyn-plectin 1f complexes.
Bottom Line: Live imaging of acetylcholine receptors (AChRs) in cultured myotubes differentiated ex vivo from immortalized plectin-deficient myoblasts revealed them to be highly mobile and unable to coalesce into stable clusters, in contrast to wild-type cells.In their phenotypic behavior, mutant mice closely mimicked EBS-MD-MyS patients, including impaired body balance, severe muscle weakness, and reduced life span.Our study demonstrates that linkage to desmin IF networks via plectin is crucial for formation and maintenance of AChR clusters, postsynaptic NMJ organization, and body locomotion.
Affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.Show MeSH
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Mentions: The inefficient AChR clustering observed in ex vivo–differentiated plectin-deficient myotubes, together with the grossly disorganized structure of NMJs typical for patients suffering from plectinopathy-associated MyS (Engel, 2012), strongly suggested that postsynaptic plectin plays a role in maintaining dense AChR clusters at the crests of sarcolemma infoldings. To examine on the organismal level whether the lack of postsynaptic plectin causes defects in NMJ morphology with consequences for muscle strength and body balance, we generated a mouse line (Pax7-Cre/cKO) in which plectin gene disruption was controlled by Pax7, a transcription factor that is expressed in muscle stem cells (Relaix et al., 2005). In contrast to a previously generated MCK-Cre/cKO mouse line (Konieczny et al., 2008), in which precursor satellite cells were exempt from ablation (allowing reexpression of plectin in adult myofibers during regeneration), Pax7-Cre/cKO mice were plectin negative not only in mature myofibers of limb muscles, but also in satellite cells (Supplemental Figure S3) and consequently at NMJs (Figure 6A). Whereas MCK-Cre/cKO mice were hardly distinguishable from their wt littermates until reaching adulthood, Pax7-Cre/cKO mice suffered from body weakness, manifesting as small size, profound kyphosis, and a survival rate of only 50% at the age of 19 wk (Figure 6, B and C).
Affiliation: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.