肌肉通過肥大及其代謝變化來適應運動訓練。神經肌肉接頭 (NMJ)是運動神經元用來控制肌肉的收縮的軸突末端結構，許多研究顯示運動訓練亦可以造成NMJ的結構變化來適應運動訓練。然而，與運動造成的肌肉肥大不同，對於運動訓練如何改變NMJ的結構我們在分子機制上仍所知之甚少。果蠅幼蟲的爬行活動已被證實能造成其NMJ的結構改變，且急性刺激果蠅幼蟲的NMJ會觸發NMJ的結構新生，藉由量化急性刺激下NMJ觸發的新生結構，這篇論文試著使用果蠅幼蟲的神經肌肉系統為模型來研究NMJ的活動依賴性結構重塑。通過急性刺激NMJ活性並同時限制肌肉的收縮，我們發現肌肉的物理性運動收縮在NMJ的活動依賴性結構重塑上扮演協助的功能。過去已知層粘連蛋白A (LanA)能通過逆行信號(Retrograde signaling)的方式抑制果蠅幼蟲NMJ的生長，而位於NMJ上層粘連蛋白A的數量則會受到幼蟲長期爬行活動的調節。在這裡，我進一步確認層粘連蛋白A能抑制NMJ的活動依賴性結構重塑，並且發現對NMJ的急性刺激能快速降低層粘連蛋白A在NMJ的濃度。此外，若肌肉的物理性收縮被抑制則粘連蛋白A在NMJ的濃度將不再受NMJ的活性影響，這說明肌肉的物理性運動收縮可能直接影響粘連蛋白A在NMJ的濃度調控，並因而影響NMJ的活動依賴性結構重塑。分子機制上，層粘連蛋白A在NMJ的濃度調控需要基質金屬蛋白酶(Matrix metalloproteinase, MMP)的參與。且抑制MMP的活性或表現亦會干擾果蠅NMJ的活動依賴性結構重塑。肌營養不良蛋白聚糖(Dystroglycan)是一個富含於肌肉細胞膜上的層粘連蛋白受體，過去研究發現，dystroglycan及相關蛋白負責將肌肉收縮過程中產生的張力分配至胞外基質網路中。這邊證明了dystroglycan也參與了果蠅NMJ的活動依賴性結構重塑，且層粘連蛋白A的活動依賴性濃度調控亦需要dystroglycan。最後我們發現dystroglycan能影響MMP在NMJ的表現量，且dystroglycan和MMP之間協同參與NMJ的活動依賴性結構重塑與層粘連蛋白A的活動依賴性濃度調控。基於這些發現，本研究認為肌肉的物理性收縮可能經過dystroglycan來影響MMP於NMJ的活性與表現來調節層粘連蛋白A的濃度，並因此影響果蠅NMJ的活動依賴性結構重塑。

Muscle adapts to exercise training through hypertrophy and changes to its metabolism. Exercise training remodels neuromuscular junctions (NMJs), through which motor neurons control muscle contraction. However, unlike muscle, how exercise contributes to the remodeling of NMJs remains poorly understood. Drosophila larval NMJs are capable of rapidly NMJ remodeling through formation of new boutons in response to acute spaced stimulation, providing a suitable platform to dissect the requirements and mechanisms of exercise-dependent NMJ remodeling. By utilizing physical and chemical ways to restrict the muscular contraction without affecting presynaptic stimulation, I show that the dynamic contraction of muscle is an important factor for activity-dependent new botuon formation at NMJs. Retrograde signaling of Laminin-A (LanA) suppresses the growth of larval NMJs, while the levels of LanA at NMJs were regulated by the long-term crawling activities of larvae. Here I confirm that LanA also suppresses the acute activity-dependent new bouton formation, and further demonstrate that the synaptic LanA levels can be rapidly downregulated by acute spaced stimulations. Moreover, the downregulation of LanA requires dynamic contraction of muscle, suggesting that LanA regulation is one of the mechanisms for dynamic muscular contraction to remodel NMJs. The activity-dependent downregulation of synaptic LanA requires matrix metalloproteinase (MMP) activity, which is also directly involved in new bouton induction. Dystroglycan (Dg), the Laminin receptor of the Dystrophin-glycoprotein complex, promotes activity-dependent new bouton formation through LanA regulation. Dg also genetically interact with MMP-1 to regulate new bouton induction, and Dg control the protein levels of MMP-1 at larval NMJs. Thus, I propose that dynamic muscle contraction promotes activity-dependent NMJ remodeling through LanA downregulation, which is mediated through Dg and MMP-1 at Drosophila larval NMJs.

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