Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet, and Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden.
FASEB J. 2020 Jun;34(6):7958-7969. doi: 10.1096/fj.201902976R. Epub 2020 Apr 15.
This study explored the muscle genome-wide response to long-term unloading (84-day bed rest) in 21 men. We hypothesized that a part of the bed rest-induced gene expression signature would be resilient to a concurrent flywheel resistance exercise (RE) countermeasure. Using DNA microarray technology analyzing 35 345 gene-level probe-sets, we identified 335 annotated probe-sets that were downregulated, and 315 that were upregulated after bed rest (P < .01). Besides a predictable differential expression of genes and pathways related to mitochondria (downregulation; false-discovery rates (FDR) <1E-04), ubiquitin system (upregulation; FDR = 3E-02), and skeletal muscle energy metabolism and structure (downregulation; FDR ≤ 3E-03), 84-day bed rest also altered circadian rhythm regulation (upregulation; FDR = 3E-02). While most of the bed rest-induced changes were counteracted by RE, 209 transcripts were resilient to the exercise countermeasure. Genes upregulated after bed rest were particularly resistant to training (P < .001 vs downregulated, non-reversed genes). Specifically, "Translation Factors," "Proteasome Degradation," "Cell Cycle," and "Nucleotide Metabolism" pathways were not normalized by RE. This study provides an unbiased high-throughput transcriptomic signature of one of the longest unloading periods in humans to date. Classical disuse-related changes in structural and metabolic genes/pathways were identified, together with a novel upregulation of circadian rhythm transcripts. In the context of previous bed rest campaigns, the latter seemed to be related to the duration of unloading, suggesting the transcriptomic machinery continues to adapt throughout extended disuse periods. Despite that the RE training offset most of the bed rest-induced muscle-phenotypic and transcriptomic alterations, we contend that the human skeletal muscle also displays a residual transcriptomic signature of unloading that is resistant to an established exercise countermeasure.
这项研究探索了 21 名男性长期（84 天卧床休息）失重对肌肉的全基因组反应。我们假设，部分卧床休息引起的基因表达特征将对同时进行的飞轮抵抗运动（RE）对策具有弹性。使用 DNA 微阵列技术分析 35345 个基因水平探针集，我们鉴定出 335 个注释探针集下调，315 个上调在卧床休息后（P<.01）。除了与线粒体（下调；错误发现率（FDR）<1E-04）、泛素系统（上调；FDR=3E-02）和骨骼肌能量代谢和结构（下调；FDR≤3E-03）相关的基因和途径的可预测差异表达外，84 天卧床休息还改变了昼夜节律调节（上调；FDR=3E-02）。虽然大部分卧床休息引起的变化都被 RE 抵消了，但 209 个转录本对运动对策具有弹性。卧床休息后上调的基因对训练特别有抵抗力（P<.001 与下调、未反转的基因相比）。具体而言，“翻译因子”、“蛋白酶体降解”、“细胞周期”和“核苷酸代谢”途径未通过 RE 正常化。这项研究提供了迄今为止人类最长卸载期之一的无偏高通量转录组特征。鉴定了与结构和代谢基因/途径相关的经典失用相关变化，以及昼夜节律转录物的新上调。在之前的卧床休息运动的背景下，后者似乎与卸载的持续时间有关，这表明转录组机制在整个延长的失用期内继续适应。尽管 RE 训练抵消了大部分卧床休息引起的肌肉表型和转录组改变，但我们认为人类骨骼肌也表现出对既定运动对策具有弹性的卸载残留转录组特征。
