Pareja-Cajiao Miguel, Gransee Heather M, Jahanian Sepideh, Sieck Gary C, Mantilla Carlos B
Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
Exp Physiol. 2025 Jan;110(1):166-178. doi: 10.1113/EP092095. Epub 2024 Nov 22.
Ageing-related neuromuscular dysfunction is associated with reduced tropomyosin-related kinase receptor subtype B (TrkB) signalling and accumulation of damaged cytoplasmic aggregates in motor neurons. Autophagy functions to remove these damaged aggregates, and we previously reported increased cervical motor neuron expression of LC3 and p62 in old age. We hypothesized that inhibition of TrkB kinase activity results in an increase in the relative expression of both LC3 and p62 in cervical motor neurons, consistent with impaired progression of autophagy. TrkB mice, which possess a mutation that renders TrkB kinase activity susceptible to rapid inhibition by 1NMPP1, were treated at 6, 18 or 24 months of age with vehicle or 1NMPP1 for 7 days. Immunofluorescence intensity was measured to determine LC3 and p62 expression in choline acetyltransferase-positive motor neurons in the cervical spinal cord. The effect of inhibiting TrkB kinase activity on progression of autophagy was age dependent. In 6-month-old mice, inhibiting TrkB kinase activity increased cervical motor neuron expression of LC3 by 11% (P < 0.001) and p62 by 8% (P = 0.019) compared with vehicle treatment. In 18- and 24-month-old mice, there was no effect of inhibiting TrkB kinase activity on motor neuron LC3 or p62 expression. We provide evidence that inhibition of TrkB signalling impairs progression of autophagy in motor neurons of young mice, similar to the response to ageing. Accordingly, a reduction of TrkB signalling in old age might contribute to neuromuscular dysfunction by impairing progression of autophagy in motor neurons.
与衰老相关的神经肌肉功能障碍与原肌球蛋白相关激酶受体B亚型（TrkB）信号传导减少以及运动神经元中受损细胞质聚集体的积累有关。自噬的功能是清除这些受损的聚集体，我们之前报道过老年时颈髓运动神经元中微管相关蛋白1轻链3（LC3）和p62的表达增加。我们假设抑制TrkB激酶活性会导致颈髓运动神经元中LC3和p62的相对表达增加，这与自噬进程受损一致。TrkB小鼠携带一种突变，使得TrkB激酶活性易于被1-氮杂环丙基甲基膦酸酯（1NMPP1）快速抑制，在6、18或24月龄时用溶剂或1NMPP1处理7天。通过测量免疫荧光强度来确定颈髓中胆碱乙酰转移酶阳性运动神经元中LC3和p62的表达。抑制TrkB激酶活性对自噬进程的影响具有年龄依赖性。与溶剂处理相比，在6月龄小鼠中，抑制TrkB激酶活性使颈髓运动神经元中LC3的表达增加了11%（P<0.001），p62的表达增加了8%（P=0.019）。在18月龄和24月龄小鼠中，抑制TrkB激酶活性对运动神经元LC3或p62的表达没有影响。我们提供的证据表明，抑制TrkB信号传导会损害幼鼠运动神经元中的自噬进程，这与衰老反应相似。因此，老年时TrkB信号传导的减少可能通过损害运动神经元中的自噬进程而导致神经肌肉功能障碍。
