Sirago Giuseppe, Candia Julián, Franchi Martino V, Sarto Fabio, Monti Elena, Toniolo Luana, Reggiani Carlo, Giacomello Emiliana, Zampieri Sandra, Hartnell Lisa M, De Vito Giuseppe, Sandri Marco, Ferrucci Luigi, Narici Marco V
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
Translational Gerontology Branch Longitudinal Studies Section, National Institute on Aging, Baltimore, MD 21224, USA.
Biology (Basel). 2023 Mar 10;12(3):431. doi: 10.3390/biology12030431.
Human skeletal muscle atrophy and a disproportionate force loss occur within a few days of unloading in space and on Earth, but the underlying mechanisms are not fully understood. Disruption of neuromuscular junction homeostasis has been proposed as one of the possible causes. Here, we investigated the potential mechanisms involved in this neuromuscular disruption induced by a 10-day unilateral lower limb suspension (ULLS) in humans. Specifically, we investigated hemichannels' upregulation, neuromuscular junction and axonal damage, neurotrophins' receptor downregulation and inflammatory transcriptional signatures. Biomarkers were evaluated at local and systemic levels. At the sarcolemmal level, changes were found to be associated with an increased expression of connexin 43 and pannexin-1. Upregulation of the inflammatory transcripts revealed by deep transcriptomics was found after 10 days of ULLS. The destabilisation of the neuromuscular junction was not accompanied by changes in the secretion of the brain-derived neurotrophic factor and neurotrophin-4, while their receptor, BDNF/NT growth factors receptor (TrkB), decreased. Furthermore, at 5 days of ULLS, there was already a significant upregulation of the serum neurofilament light chain concentration, an established clinical biomarker of axonal injury. At 10 days of ULLS, other biomarkers of early denervation processes appeared. Hence, short periods of muscle unloading induce sarcolemmal hemichannels upregulation, inflammatory transcripts upregulation, neuromuscular junction instability and axonal damage.
在太空和地球上，人体骨骼肌萎缩和不成比例的力量丧失会在卸载后的几天内发生，但其潜在机制尚未完全明确。神经肌肉接头稳态的破坏被认为是可能的原因之一。在此，我们研究了人类单侧下肢悬吊（ULLS）10天所诱导的这种神经肌肉破坏的潜在机制。具体而言，我们研究了半通道上调、神经肌肉接头和轴突损伤、神经营养因子受体下调以及炎症转录特征。在局部和全身水平评估生物标志物。在肌膜水平，发现变化与连接蛋白43和泛连接蛋白-1的表达增加有关。ULLS 10天后，通过深度转录组学揭示了炎症转录本的上调。神经肌肉接头的不稳定并未伴随着脑源性神经营养因子和神经营养因子-4分泌的变化，而它们的受体，BDNF/NT生长因子受体（TrkB）减少。此外，在ULLS 5天时，血清神经丝轻链浓度已经显著上调，这是一种已确立的轴突损伤临床生物标志物。在ULLS 10天时，出现了早期去神经支配过程的其他生物标志物。因此，短时间的肌肉卸载会诱导肌膜半通道上调、炎症转录本上调、神经肌肉接头不稳定和轴突损伤。
