長鏈非編碼TERRA RNA在人類老化過程中扮演的角色

Abstract

端粒是個位於染色體末端，具有保護染色體防止被降解的高重複性DNA結構。現今研究已知，隨著年紀的增長，端粒的長度也會隨著每次的細胞分裂而隨之縮短。因此，端粒的長度也被視為細胞老化的重要指標。而近期研究指出，一段從亞端粒區（Subtelomeric）轉錄出來的長鏈非編碼（未轉譯成蛋白質表現基因的RNA）端粒重複序列RNA（TERRA），在酵母菌實驗中有參與細胞老化的過程。但TERRA在人類中扮演何種調控角色仍是存在許多未知的。因此，我們將著重於研究老化與其相關疾病在衰老的過程中，端粒長度以及TERRA表現量的改變。肌少症（Sarcopenia）是近期大家熱衷於討論的老化相關疾病，特徵是骨骼肌質量的流失以及功能強度下降。為此，我們分別收集了年輕（< 65歲），老年（≥ 65歲），和肌少症（≥ 65歲）的血液白細胞層（Buffy coat）。我們將肌少症病患介入為期12週，每週2次的肌力訓練，並在介入前與介入後分別抽取血液白細胞層。實驗結果發現，端粒長度確實在老化後有明顯地縮短，但患有肌少症的老人和一般老年人端粒長度並沒有差異，也沒有在運動後發生改變。但有趣的是，TERRA表現量卻在一般老年有顯著高於年輕以及肌少症者的情況，而肌少症者介入短時間的肌肉訓練後TERRA表現量有些微上升的趨勢。這些結果顯示TERRA轉錄會隨著年紀而上升，但因肌少症導致轉錄量下降。不過短時間的肌肉訓練可以使肌少症者轉錄量些微上升。

Telomeres contain repetitive DNA sequences that can form a capping structure to protect linear chromosome ends from degradation. As human aging, telomere length will be shortened as cells divide. Therefore, telomere length has been considered as a marker of cellular aging. Recent studies have reported that Telomeric Repeat-Containing RNAs (TERRA), a long non-coding RNA, which is transcribed from the subtelomeric regions toward telomeres may participate in cellular aging in budding yeast. But the function of TERRA in humans is still largely unknown. Here I focus on TERRA expression and telomere length during human natural aging, and in patients with an aging-associated disease sarcopenia, a syndrome characterized by the loss of skeletal muscle mass and strength. To study TERRA expression and telomere length, we collected RNA and genomic DNA from buffy coats of young (< 65 years old), elderly (≥ 65 years old), and elderly patient (≥ 65 years old) groups. The buffy coat samples were also collected from patients before and after muscle training, which performed 2 times a week for twelve weeks. Compared to the young group, the telomere length of elderly was significantly decreased, but there was no significant difference between pre- and post-exercise elderly patient groups. Interestingly, elderly control group showed a higher TERRA level than young control and case groups, indicating that TERRA transcription increased during aging, but decreased in sarcopenia patients. Muscle training for twelve weeks may slightly rescue the TERRA transcription in sarcopenia patients. These results reveal that TERRA expression is associated with human aging and downregulated in sarcopenia patients, and muscle training could upregulate TERRA expression.