National Institute on Aging, Intramural Research Program, Baltimore, MD (L.F., J.C., C.U.-M., A.L., N.B., M.K., S.D., M.G., R.M.).
Department of Physiology and Aging, University of Florida, Institute on Aging, Gainesville, FL (C.L., S.W.).
Circ Res. 2023 May 26;132(11):1428-1443. doi: 10.1161/CIRCRESAHA.122.322325. Epub 2023 May 8.
Few effective therapies exist to improve lower extremity muscle pathology and mobility loss due to peripheral artery disease (PAD), in part because mechanisms associated with functional impairment remain unclear.
To better understand mechanisms of muscle impairment in PAD, we performed in-depth transcriptomic and proteomic analyses on gastrocnemius muscle biopsies from 31 PAD participants (mean age, 69.9 years) and 29 age- and sex-matched non-PAD controls (mean age, 70.0 years) free of diabetes or limb-threatening ischemia.
Transcriptomic and proteomic analyses suggested activation of hypoxia-compensatory mechanisms in PAD muscle, including inflammation, fibrosis, apoptosis, angiogenesis, unfolded protein response, and nerve and muscle repair. Stoichiometric proportions of mitochondrial respiratory proteins were aberrant in PAD compared to non-PAD, suggesting that respiratory proteins not in complete functional units are not removed by mitophagy, likely contributing to abnormal mitochondrial activity. Supporting this hypothesis, greater mitochondrial respiratory protein abundance was significantly associated with greater complex II and complex IV respiratory activity in non-PAD but not in PAD. Rate-limiting glycolytic enzymes, such as hexokinase and pyruvate kinase, were less abundant in muscle of people with PAD compared with non-PAD participants, suggesting diminished glucose metabolism.
In PAD muscle, hypoxia induces accumulation of mitochondria respiratory proteins, reduced activity of rate-limiting glycolytic enzymes, and an enhanced integrated stress response that modulates protein translation. These mechanisms may serve as targets for disease modification.
由于外周动脉疾病（PAD），下肢肌肉病理和运动功能丧失的有效治疗方法很少，部分原因是与功能障碍相关的机制仍不清楚。
为了更好地了解 PAD 肌肉损伤的机制，我们对 31 名 PAD 参与者（平均年龄 69.9 岁）和 29 名年龄和性别匹配的非 PAD 对照者（平均年龄 70.0 岁）的腓肠肌活检组织进行了深入的转录组和蛋白质组分析，这些对照者无糖尿病或肢体缺血威胁。
转录组和蛋白质组分析表明，PAD 肌肉中存在缺氧补偿机制的激活，包括炎症、纤维化、细胞凋亡、血管生成、未折叠蛋白反应以及神经和肌肉修复。与非 PAD 相比，PAD 中的线粒体呼吸蛋白的化学计量比例异常，这表明不是完整功能单位的呼吸蛋白不能通过线粒体自噬去除，这可能导致异常的线粒体活性。支持这一假说，非 PAD 中更大的线粒体呼吸蛋白丰度与更大的复合物 II 和复合物 IV 呼吸活性显著相关，但在 PAD 中则不然。与非 PAD 参与者相比，PAD 肌肉中的限速糖酵解酶（如己糖激酶和丙酮酸激酶）含量较低，表明葡萄糖代谢减少。
在 PAD 肌肉中，缺氧会导致线粒体呼吸蛋白的积累、限速糖酵解酶活性的降低以及整合应激反应的增强，从而调节蛋白质翻译。这些机制可能成为疾病修饰的靶点。
