During aging, skeletal muscles become atrophic and lose contractile force. Aging can also impact the neuromuscular junction (NMJ), a synapse that transmits signals from motoneurons to muscle fibers to control muscle contraction. However, in contrast to muscle aging that has been studied extensively, less is known about the molecular mechanisms of NMJ aging although its structure and function are impaired in aged animals. To this end, we performed RNA sequencing (RNA-seq) analysis to identify genes whose expression in synapse-rich region is altered. Gene ontology (GO) analysis highlighted genes relating to nuclear structure or function. In particular, lamin A/C, an intermediate filament protein critical for the interphase nuclear architecture, was reduced. Remarkably, mutation of lamin A/C in muscles or motoneurons had no effect on NMJ formation in either sex of mice, but the muscle mutation caused progressive denervation, acetylcholine receptor (AChR) cluster fragmentation, and neuromuscular dysfunction. Interestingly, rapsyn, a protein critical to AChR clustering, was reduced in mutant muscle cells; and expressing rapsyn in muscles attenuated NMJ deficits of HSA-Lmna–/– mice. These results reveal a role of lamin A/C in NMJ maintenance and suggest that nuclear dysfunction or deficiency may contribute to NMJ deficits in aged muscles.

SIGNIFICANCE STATEMENT This study provides evidence that lamin A/C, a scaffolding component of the nuclear envelope, is critical to maintaining the NMJ in mice. Its muscle-specific mutation led to progressive NMJ degeneration in vivo. We showed that the mutation reduced the level of rapsyn, a protein necessary for acetylcholine receptor (AChR) clustering; and expression of rapsyn in muscles attenuated NMJ deficits of HSA-Lmna–/– mice. These results reveal a role of lamin A/C in NMJ maintenance and suggest that nuclear dysfunction or deficiency may contribute to NMJ deficits in aged muscles.

在衰老过程中，骨骼肌萎缩并失去收缩力。衰老还会影响神经肌肉接头（NMJ），神经突触是将信号从运动神经元传递到肌肉纤维以控制肌肉收缩的突触。然而，与已经被广泛研究的肌肉衰老相反，尽管NMJ衰老的分子机理在衰老动物中受损，但对它的分子机制知之甚少。为此，我们进行了RNA测序（RNA-seq）分析，以鉴定在富含突触的区域中表达发生变化的基因。基因本体论（GO）分析突出显示了与核结构或功能有关的基因。特别是减少了lamin A / C（一种对相间核结构至关重要的中间丝蛋白）。值得注意的是 肌肉或运动神经元中lamin A / C的突变对任何性别的小鼠的NMJ形成均无影响，但该肌肉突变导致进行性神经支配，乙酰胆碱受体（AChR）簇断裂和神经肌肉功能障碍。有趣的是，rapsyn（一种对AChR聚簇至关重要的蛋白质）在突变型肌肉细胞中减少了。并在肌肉中表达rapsyn减轻了NMJ的缺陷。HSA-Lmna – / –小鼠。这些结果揭示了核纤层蛋白A / C在NMJ维持中的作用，并表明核功能障碍或缺乏可能导致老年肌肉的NMJ缺乏。

重要性声明这项研究提供了证据，证明核纤层蛋白支架蛋白Lamin A / C对维持小鼠NMJ至关重要。其肌肉特异性突变导致体内进行性NMJ变性。我们表明，该突变降低了rapsyn的水平，rapsyn是乙酰胆碱受体（AChR）聚簇所必需的蛋白质。肌肉中rapsyn的表达和表达减弱了HSA-Lmna – / –小鼠的NMJ缺陷。这些结果揭示了核纤层蛋白A / C在NMJ维持中的作用，并表明核功能障碍或缺乏可能导致老年肌肉的NMJ缺乏。