BackgroundAstronauts in Earth's orbit experience microgravity, resulting in a decline of skeletal muscle mass and function. On Earth, models simulating microgravity have shown that the extent of the loss in muscle force is greater than the loss in muscle mass. The reasons behind this disproportionate loss of muscle force are still poorly understood. In the present study, we hypothesize that alongside the loss in skeletal muscle mass, modifications in the expression profile of genes encoding critical determinants of resting membrane potential, excitation‐contraction coupling and Ca2+ handling contribute to the decline in skeletal muscle force.MethodsHealthy male volunteers (n = 18) participated in a 5‐day dry immersion (DI) study, an Earth‐based model of simulated microgravity. Muscle force measurement and MRI analysis of the cross‐sectional area of thigh muscles were performed before and after DI. Biopsies of the vastus lateralis skeletal muscle performed before and after DI were used for the determination Ca2+ properties of isolated muscle fibres, molecular and biochemical analyses.ResultsThe extent of the decline in force, measured as maximal voluntary contraction of knee extensors (−11.1%, P < 0.01) was higher than the decline in muscle mass (−2.5%, P < 0.01). The decline in muscle mass was molecularly supported by a significant repression of the anabolic IGF‐1/Akt/mTOR pathway (−19.9% and −40.9% in 4E‐BP1 and RPS6 phosphorylation, respectively), a transcriptional downregulation of the autophagy‐lysosome pathway and a downregulation in the mRNA levels of myofibrillar protein slow isoforms. At the single fibre level, biochemical and tension‐pCa curve analyses showed that the loss in force was independent of fibre type (−11% and −12.3% in slow and fast fibres, respectively) and Ca2+ activation properties. Finally, we showed a significant remodelling in the expression of critical players of resting membrane potential (aquaporin 4: −24.9%, ATP1A2: +50.4%), excitation‐contraction coupling (CHRNA1: +75.1%, CACNA2D1: −23.5%, JPH2: −24.2%, TRDN: −15.6%, S100A1: +27.2%), and Ca2+ handling (ATP2A2: −32.5%, CASQ1: −15%, ORAI1: −36.2%, ATP2B1: −19.1%).ConclusionsThese findings provide evidence that a deregulation in the expression profile of critical molecular determinants of resting membrane potential, excitation‐contraction coupling, and Ca2+ handling could be involved in the loss of muscle force induced by DI. They also provide the paradigm for the understanding of muscle force loss during prolonged bed rest periods as those encountered in intensive care unit.

中文翻译：

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人体干浸 5 天后骨骼肌力损失的分子决定因素


背景地球轨道上的宇航员受到微重力的影响，导致骨骼肌质量和功能下降。在地球上，模拟微重力的模型表明，肌肉力量的损失程度大于肌肉质量的损失。这种不成比例的肌肉力量损失背后的原因仍然知之甚少。在本研究中，我们假设除了骨骼肌质量的损失外，编码静息膜电位关键决定因素、兴奋-收缩耦合和 Ca2+ 处理的基因表达谱的改变也会导致骨骼肌力量的下降。方法健康男性志愿者 （n = 18） 参加了一项为期 5 天的干浸 （DI） 研究，这是一种基于地球的模拟微重力模型。在 DI 之前和之后进行肌肉力量测量和大腿肌肉横截面积的 MRI 分析。在 DI 之前和之后进行的股外侧肌骨骼肌活检用于测定离体肌纤维的 Ca2+ 特性、分子和生化分析。结果以膝关节伸肌的最大自主收缩量（-11.1%，P < 0.01）衡量的力量下降程度高于肌肉质量的下降（-2.5%，P < 0.01）。肌肉质量的下降由合成代谢 IGF-1/Akt/mTOR 通路的显着抑制（4E-BP1 和 RPS6 磷酸化分别为 -19.9% 和 -40.9%）、自噬-溶酶体通路的转录下调和肌原纤维蛋白慢亚型 mRNA 水平的下调在分子上支持。在单纤维水平上，生化和张力 pCa 曲线分析表明，力损失与纤维类型无关 （-11% 和 -12.慢纤维和快纤维分别为 3%）和 Ca2+ 活化特性。最后，我们显示静息膜电位（水通道蛋白 4：-24.9%，ATP1A2：+50.4%）、兴奋-收缩耦合（CHRNA1：+75.1%，CACNA2D1：-23.5%，JPH2：-24.2%，TRDN：-15.6%，S100A1：+27.2%）和 Ca2+ 处理（ATP2A2：-32.5%，CASQ1：-15%，ORAI1：-36.2%，ATP2B1：-19.1%）的关键参与者的表达发生显着重塑。结论这些发现提供了证据，表明静息膜电位、兴奋-收缩耦合和 Ca2+ 处理的关键分子决定因素表达谱的失调可能与 DI 诱导的肌肉力量损失有关。它们还为理解长时间卧床休息期间的肌肉力量损失提供了范例，就像在重症监护病房中遇到的那样。