Synaptic FGFs are required and sufficient to maintain and repair aged NMJs

 描述(申请人提供)：运动功能随着年龄的增长而下降，导致行动不便，丧失独立性，对损伤和疾病的易感性增加。许多研究试图确定导致神经肌肉系统老化的细胞和分子因素。最近的发现有力地表明，神经肌肉接头的结构和分子变化发生在运动神经元和骨骼肌纤维表现出明显的与年龄相关的病理变化之前。因此，神经肌肉连接处的有害变化可能会在衰老过程中引发缓慢但持续的运动功能丧失。虽然众所周知，维持和修复神经肌肉连接需要肌源性因子，但这些因子的特性仍然难以捉摸。为此，我们采取了不同的、但互为补充的方法来确定肌肉衍生因子，这些因子的功能是维持神经肌肉接头的结构和功能完整性，使其免受衰老的破坏。在这方面，我们收集了初步的数据，表明成纤维细胞生长因子信号通路的三个成员，成纤维细胞生长因子-7/10/22和成纤维细胞生长因子结合蛋白(FGFBP1)是保护神经肌肉接头免受正常衰老、ALS引起的突变和周围神经损伤所产生的损伤的有希望的候选分子。在小鼠中，缺失成纤维细胞生长因子-22会导致神经肌肉接头过早老化。它还会推迟骨骼肌在受伤后的神经再支配。同样，FGFBP1的减少会加速神经肌肉接头的年龄相关变化，并损害年轻成年小鼠的运动功能。重要的是，将FGFBP1和FGFBP1引入失神经肌肉可以加速它们的神经再支配，进一步表明FGFBP1和FGFBP1具有修复神经肌肉连接的功能。我们坚信，拟议中的实验可能会带来新的分子靶点，用于开发治疗干预措施，以保护和修复神经肌肉接头，从而减缓、防止甚至逆转运动系统的衰老。

 DESCRIPTION (provided by applicant): Motor function declines with aging resulting in impaired mobility, loss of independence and increased susceptibility to injury and diseases. Many studies have sought to determine the cellular and molecular factors that contribute to aging of the neuromuscular system. Recent findings strongly suggest that structural and molecular alterations at neuromuscular junctions occur before motor neurons and skeletal muscle fibers exhibit obvious age-related pathological changes. Thus, deleterious changes at the neuromuscular junction may trigger the slow but consistent loss of motor function during aging. While it is known that muscle-derived factors are required to maintain and repair the neuromuscular junction, the identity of such factors has remained elusive. To this end, we have taken varied, yet complementary, approaches to identify muscle- derived factors that function to maintain the structural and functional integrity of neuromuscular junctions from the ravages of aging. In this regard, we have gathered preliminary data suggesting that three members of the fibroblast growth factor (FGF) signaling pathway, FGF-7/10/22, and a FGF-binding protein (FGFBP1) are promising candidate molecules for protecting neuromuscular junctions from insults emanating from normal aging, ALS-causing mutations and injury to peripheral nerves. In mice, deletion of FGF-22 results in premature aging of the neuromuscular junction. It also delays reinnervation of skeletal muscles after injury. Similarly, a reduction in FGFBP1 accelerates age-associated changes at neuromuscular junctions and compromises motor function in young adult mice. Importantly, introducing FGFBP1 and FGF-22 into denervated muscles accelerates their reinnervation, further indicating that FGF-22 and FGFBP1 function to repair the neuromuscular junction. We strongly believe that the proposed experiments could lead to new molecular targets for developing therapeutic interventions to protect and repair the neuromuscular junction, and thus slow, prevent or even reverse aging of the motor system.