Department of Biology, Baylor University, Waco, Texas.
Department of Surgery, University of Texas Health Science Center San Antonio, San Antonio, Texas.
Transl Res. 2022 Aug;246:66-77. doi: 10.1016/j.trsl.2022.03.003. Epub 2022 Mar 12.
Previous studies have demonstrated that circulating microRNA (miR)-210 levels are elevated in peripheral artery disease (PAD) patients. MiR-210 is known to be a negative regulator of mitochondrial respiration; however, the relationship between miR-210 and mitochondrial function has yet to be studied in PAD. We aimed to compare skeletal muscle miR-210 expression of PAD patients to non-PAD controls (CON) and to examine the relationship between miR-210 expression and mitochondrial function. Skeletal muscle biopsies from CON (n = 20), intermittent claudication (IC) patients (n = 20), and critical limb ischemia (CLI) patients (n = 20) were analyzed by high-resolution respirometry to measure mitochondrial respiration of permeabilized fibers. Samples were also analyzed for miR-210 expression by real-time PCR. MiR-210 expression was significantly elevated in IC and CLI muscle compared to CON (P = 0.008 and P < 0.001, respectively). Mitochondrial respiration of electron transport chain (ETC) Complexes II (P = 0.001) and IV (P < 0.001) were significantly reduced in IC patients. Further, CLI patients demonstrated significant reductions in respiration during Complexes I (state 2: P = 0.04, state 3: P = 0.003), combined I and II (P < 0.001), II (P < 0.001), and IV (P < 0.001). The expression of the miR-210 targets, cytochrome c oxidase assembly factor heme A: farnesyltransferase (COX10), and iron-sulfur cluster assembly enzyme (ISCU) were down-regulated in PAD muscle. MiR-210 may play a role in the cellular adaptation to hypoxia and may be involved in the metabolic myopathy associated with PAD.
先前的研究表明，外周动脉疾病（PAD）患者外周循环中的 microRNA（miR）-210 水平升高。已知 miR-210 是线粒体呼吸的负调节剂；然而，miR-210 与 PAD 中线粒体功能之间的关系尚未得到研究。我们旨在比较 PAD 患者与非 PAD 对照组（CON）的骨骼肌 miR-210 表达，并研究 miR-210 表达与线粒体功能之间的关系。通过高分辨率呼吸仪分析 CON（n=20）、间歇性跛行（IC）患者（n=20）和严重肢体缺血（CLI）患者（n=20）的骨骼肌活检，以测量通透纤维的线粒体呼吸。还通过实时 PCR 分析样品中的 miR-210 表达。与 CON 相比，IC 和 CLI 肌肉中的 miR-210 表达显著升高（P=0.008 和 P<0.001）。IC 患者电子传递链（ETC）复合物 II（P=0.001）和 IV（P<0.001）的线粒体呼吸显著降低。此外，CLI 患者在复合物 I（状态 2：P=0.04，状态 3：P=0.003）、复合物 I 和 II（P<0.001）、复合物 II（P<0.001）和 IV（P<0.001）期间呼吸显著降低。miR-210 的靶标细胞色素 c 氧化酶组装因子血红素 A：法呢基转移酶（COX10）和铁硫簇组装酶（ISCU）的表达在 PAD 肌肉中下调。miR-210 可能在细胞适应缺氧中发挥作用，并可能与 PAD 相关的代谢性肌病有关。
