Department of Physical Therapy and Athletic Training, University of Utah , Salt Lake City, Utah.
Bioinformatics Shared Resource at the Huntsman Cancer Institute , Salt Lake City, Utah.
J Appl Physiol (1985). 2019 Apr 1;126(4):894-902. doi: 10.1152/japplphysiol.00811.2018. Epub 2019 Jan 3.
Short-term muscle disuse induces significant muscle loss in older adults and in some reports may be more accelerated with aging. Identifying muscle transcriptional events in response to bed rest may help identify therapeutic targets to offset muscle loss. Therefore, we compared the muscle transcriptome between young and older adults after bed rest and identified candidate targets related to changes in muscle loss. RNA was sequenced (HiSeq, Illumina; DESeq, R) from muscle biopsies obtained from young [ n = 9; 23 yr (SD 3)] and older [ n = 18; 68 yr (SD 6)] adults before and after 5-day bed rest. Significantly altered pathways in both young and old subjects relating to mechanosensing and cell adhesion (Actin Cytoskeleton Signaling, ILK Signaling, RhoA Signaling, and Integrin Signaling) were altered (activation z score) to a greater extent in old subjects. Hepatic Fibrosis/Hepatic Stellate Cell Activation was the top regulated pathway significantly altered only in the old. Fifty-one differentially regulated genes were only altered in the young after bed rest and resembled a gene expression profile like that in the old at baseline. Inflammation and muscle wasting genes (CXCL2, GADD45A) were uniquely increased in the old after bed rest, and the macrophage gene MAFB decreased in the old and correlated with the change in leg lean mass. In summary, skeletal muscle dysregulation during bed rest in the old may be driven by alterations in molecules related to fibrosis, inflammation, and cell adhesion. This information may aid in the development of mechanistic-based therapies to combat muscle atrophy during short-term disuse. NEW & NOTEWORTHY Using RNA sequencing and bioinformatics approaches, we identified that older adult skeletal muscle was characterized by dysregulated pathways associated with fibrosis, inflammation (upregulated), and cell adhesion and mechanosensing (downregulated) pathways, with a subset of genes differentially regulated in old and young muscle after bed rest that may describe predisposition to muscle loss. Unique upregulated genes only expressed in old muscle after bed rest indicated increased inflammation and muscle wasting (CXCL2, GADD45A) and decreased MAFB correlated with the change in leg lean mass.
短期肌肉失用会导致老年人肌肉大量流失，在某些报告中，随着年龄的增长，肌肉流失的速度可能会加快。鉴定卧床休息引起的肌肉转录事件可能有助于确定治疗靶点，以抵消肌肉流失。因此，我们比较了卧床休息前后年轻和老年人大腿肌肉的转录组，鉴定了与肌肉丢失变化相关的候选靶点。从年轻（n=9；23 岁（SD3））和老年（n=18；68 岁（SD6））成年人卧床休息前和卧床休息 5 天后获得的肌肉活检中提取 RNA（HiSeq，Illumina；DESeq，R）。年轻和老年受试者中与机械感觉和细胞黏附相关的显著改变的途径（肌动蛋白细胞骨架信号、ILK 信号、RhoA 信号和整合素信号）在老年受试者中改变（激活 z 评分）更为明显。肝纤维化/肝星状细胞激活是唯一在老年受试者中显著改变的调控途径。51 个差异调节基因仅在卧床休息后在年轻受试者中改变，且与基线时老年受试者的基因表达谱相似。炎症和肌肉消耗基因（CXCL2、GADD45A）在卧床休息后仅在老年受试者中增加，而巨噬细胞基因 MAFB 在老年受试者中减少，与腿部瘦体重的变化相关。总之，卧床休息期间老年人大腿肌肉的失调可能是由与纤维化、炎症和细胞黏附相关的分子改变所驱动的。这些信息可能有助于开发基于机制的疗法，以对抗短期失用引起的肌肉萎缩。
