Long Non-coding RNA MALAT1 Is Depleted With Age in Skeletal Muscle in vivo and MALAT1 Silencing Increases Expression of TGF-β1 in vitro.
Long Non-coding RNA MALAT1 Is Depleted With Age in Skeletal Muscle in vivo and MALAT1 Silencing Increases Expression of TGF-β1 in vitro.
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DOI：
10.3389/fphys.2021.742004
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发表时间：
2021
影响因子：
4
通讯作者：
Hamrick MW
中科院分区：
文献类型：
--
作者：
Ruan L;Mendhe B;Parker E;Kent A;Isales CM;Hill WD;McGee-Lawrence M;Fulzele S;Hamrick MW
长非编码 RNA (lncRNA) 被认为充当 microRNA 的“海绵”，但这种竞争性内源 RNA (ceRNA) 在肌肉衰老中的作用尚不清楚。因此，我们在年轻（4-6 个月）和老年（22-24）雄性和雌性小鼠的骨骼肌中检查了 lncRNA MALAT1 的表达，在计算机中预测它会结合衰老相关的 microRNA miR-34a-5p。结果表明，小鼠骨骼肌中 lncRNA MALAT1 表达随着年龄的增长而显着降低，这与 miR-34a-5p 表达与年龄相关的增加相一致。使用小鼠 C2C12 成肌细胞的体外研究表明，使用 siRNA 沉默 MALAT1 会增加 miR-34a 表达，这与 MALAT1 作为 miR-34a-5p 活性抑制剂的作用一致。众所周知，肌肉中的活性氧 (ROS) 水平会随着年龄的增长而增加，因此我们用过氧化氢（10 和 100 μM）处理 C2C12 细胞，以检查 MALAT1 表达的变化。 H2O2 处理后 MALAT1 表达显着降低，但 p53 siRNA 减弱了这种效应。最后，miR-34a-5p 与组织纤维化有关，因此我们评估了 MALAT1 沉默后 TGF-β1 的表达。 MALAT1 siRNA 显着增加 C2C12 细胞中 TGF-β1 的表达。这些发现表明，由 ROS 介导的年龄相关纤维化和肌肉萎缩可能至少部分是由于 ceRNA MALAT1 耗竭导致 miR-34a“海绵作用”下降而导致 miR-34a 生物利用度增加所致。因此，MALAT1 和 miR-34a 之间的串扰可能代表了随着衰老而改善肌肉功能的治疗靶点。
Long non-coding RNAs (lncRNAs) are thought to function as “sponges” for microRNAs, but a role for such competing endogenous RNAs (ceRNAs) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4–6 months) and aged (22–24) male and female mice the expression of lncRNA MALAT1, which is predicted in silico to bind the senescence-associated microRNA miR-34a-5p. Results indicate a significant decrease in lncRNA MALAT1 expression in mouse skeletal muscle with age that coincides with an age-related increase in miR-34a-5p expression. In vitro studies using mouse C2C12 myoblasts demonstrate that MALAT1 silencing using siRNA increases miR-34a expression, consistent with a role for MALAT1 as an inhibitor of miR-34a-5p activity. Levels of reactive oxygen species (ROS) are known to increase in muscle with age, and so we treated C2C12 cells with hydrogen peroxide (10 and 100 μM) to examine changes in MALAT1 expression. MALAT1 expression decreased significantly with H2O2 treatment, but this effect was attenuated with p53 siRNA. Finally, miR-34a-5p is implicated in tissue fibrosis, and so we assessed the expression of TGF-β1 after MALAT1 silencing. MALAT1 siRNA significantly increased the expression of TGF-β1 in C2C12 cells. These findings suggest that age-related fibrosis and muscle atrophy mediated by ROS may result at least in part from an increase in miR-34a bioavailability resulting from a decline in miR-34a “sponging” due to ceRNA MALAT1 depletion. Crosstalk between MALAT1 and miR-34a may therefore represent a therapeutic target for improving muscle function with aging.
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影响因子：
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作者：
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影响因子：
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