Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis
Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis
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DOI：
10.1152/japplphysiol.00296.2015
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发表时间：
2015-08-15
影响因子：
3.3
通讯作者：
McCarthy, John J.
中科院分区：
文献类型：
--
作者：
Kirby, Tyler J.;Lee, Jonah D.;McCarthy, John J.
众所周知，老年人骨骼肌响应生长刺激而肥大的能力会受到损害。我们假设，蛋白质编码基因的表达因肥大刺激而发生变化，导致随着衰老而观察到的肥大减弱。为了检验这一假设，我们通过对 5 个月和 25 个月大的小鼠的跖肌进行微阵列分析来确定基因表达，这些小鼠接受了 1、3、5、7、10 和 14 天的增效剂消融以诱导肥大。总体而言，1,607 个基因被确定为在年轻组和老年组之间随时间进程存在差异表达；然而，基因表达的差异不大，聚类分析显示两组之间的表达模式相似。尽管老年组的核糖体蛋白基因表达较高，但与年轻小鼠相比，老年小鼠骨骼肌中的核糖体生物发生在对肥大刺激的反应中显着减弱（分别是50％和2.5倍）。老年小鼠肌肉肥大中前 47S 核糖体 RNA (rRNA) 表达未能上调，表明 RNA 聚合酶 I 的 rDNA 转录受损。与我们的假设相反，该研究的结果表明，核糖体生物合成受损是老年小鼠骨骼肌肥大反应减弱的主要因素，而不是蛋白质编码基因表达的显着差异。衰老肌肉中总 RNA、前 47S rRNA 和 28S rRNA 表达的增加减少表明核糖体生物发生的主要功能障碍发生在 rRNA 转录和加工水平。
The ability of skeletal muscle to hypertrophy in response to a growth stimulus is known to be compromised in older individuals. We hypothesized that a change in the expression of protein-encoding genes in response to a hypertrophic stimulus contributes to the blunted hypertrophy observed with aging. To test this hypothesis, we determined gene expression by microarray analysis of plantaris muscle from 5- and 25-mo-old mice subjected to 1, 3, 5, 7, 10, and 14 days of synergist ablation to induce hypertrophy. Overall, 1,607 genes were identified as being differentially expressed across the time course between young and old groups; however, the difference in gene expression was modest, with cluster analysis showing a similar pattern of expression between the two groups. Despite ribosome protein gene expression being higher in the aged group, ribosome biogenesis was significantly blunted in the skeletal muscle of aged mice compared with mice young in response to the hypertrophic stimulus (50% vs. 2.5-fold, respectively). The failure to upregulate pre-47S ribosomal RNA (rRNA) expression in muscle undergoing hypertrophy of old mice indicated that rDNA transcription by RNA polymerase I was impaired. Contrary to our hypothesis, the findings of the study suggest that impaired ribosome biogenesis was a primary factor underlying the blunted hypertrophic response observed in skeletal muscle of old mice rather than dramatic differences in the expression of protein-encoding genes. The diminished increase in total RNA, pre-47S rRNA, and 28S rRNA expression in aged muscle suggest that the primary dysfunction in ribosome biogenesis occurs at the level of rRNA transcription and processing.