Neuromuscular junctions are stable in patients with cancer cachexia
Neuromuscular junctions are stable in patients with cancer cachexia
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DOI：
10.1172/jci128411
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发表时间：
2020-03-02
影响因子：
15.9
通讯作者：
Gillingwater, Thomas H.
中科院分区：
文献类型：
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作者：
Boehm, Ines;Miller, Janice;Gillingwater, Thomas H.
癌症恶病质是患者发病率和死亡率的主要原因，没有有效的治疗或管理策略。尽管恶病质的病理生理学特征与许多神经肌肉萎缩的情况相同，包括与年龄相关的石棺减少，但恶病质的机制仍然知之甚少。对相关条件的研究表明，神经肌肉接头(NMJ)的病理靶向可能在恶病质中发挥关键作用，但这一点尚未在人类患者中进行调查。在这里，我们对接受上消化道癌症手术的患者的腹直肌NMJ进行了高分辨率的形态分析，并与对照组(N=30；n=1,165 NMJ)进行了比较。癌症患者包括恶病质和体重稳定型疾病。尽管恶病质患者存在低的骨骼肌指数和显著的肌纤维萎缩(P<；0.0001)，但NMJ的形态是完全保守的。在测量的突触前和突触后的变量中，没有观察到任何显著的差异。我们的结论是，在癌症和恶病质中，NMJ在腹直肌中保持结构完整，这表明骨骼肌的失神经不是发病的主要驱动因素。NMJ病理的缺失与相关疾病的发现形成鲜明对比，如年龄相关性石棺减少，并支持这样的假设，即骨骼肌内的内在变化独立于运动神经元的任何变化，代表癌症恶病质的神经肌肉病理的主要部位。
Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.