Kosmac Kate, Joshi Jai K, McDermott Mary M, Stewart Jada C, Zhang Dongxue, Xu Shujun, Ho Karen J, Sufit Robert, Ferrucci Luigi, Peterson Charlotte A, Ismaeel Ahmed
Department of Physical Therapy, Augusta University, Augusta, GA.
Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY.
JVS Vasc Sci. 2025 Jul 18;6:100294. doi: 10.1016/j.jvssci.2025.100294. eCollection 2025.
In people with peripheral artery disease (PAD), the Telmisartan Plus Exercise to Improve Functioning in Peripheral Artery Disease (TELEX) randomized clinical trial tested whether telmisartan (TEL), with or without exercise, significantly improved 6-minute walk distance at 6-month follow-up, compared with placebo (PLA). This study investigated the effects of TEL on exploratory muscle biopsy outcomes of muscle cellular characteristics (myofiber size, satellite cell content, capillary density, extracellular matrix, and collagen area) and molecular characteristics (cell-specific transcriptomics) in people undergoing supervised exercise in the TELEX Trial.
Baseline and 6-month follow-up muscle biopsies were obtained from 13 participants with PAD in the TELEX trial randomized to exercise + TEL (n = 6) or exercise + PLA (n = 7). Immunohistochemistry was used to measure muscle cellular characteristics, and the GeoMx digital spatial profiling system was used for transcriptomic analyses of alpha-smooth muscle actin (α-SMA)-positive and α-SMA-negative cells (primarily myofibers).
Compared with exercise + PLA, exercise + TEL increased mean myofiber cross-sectional area (+2175 μm; 95% confidence interval, -266 to 4615; = .04) and the number of satellite cells associated with type II myofibers (+17; 95% confidence interval, -1 to 35; = .03). In α-SMA-negative cells, exercise + TEL upregulated peroxisome proliferator-activated receptor gamma activation-related pathways, including nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling ( = .008), and fatty acid oxidation ( = .011). Exercise + TEL also reduced myostatin expression relative to exercise + PLA in α-SMA-negative cells (Log2fold-change = -1.24; false discovery rate = 0.010).
TEL may influence the effects of exercise on muscle in individuals with PAD by reducing myostatin expression, increasing myofiber size, and increasing activation of peroxisome proliferator-activated receptor gamma. Further study is needed to confirm these findings.
在患有外周动脉疾病（PAD）的人群中，替米沙坦联合运动改善外周动脉疾病功能（TELEX）随机临床试验测试了与安慰剂（PLA）相比，替米沙坦（TEL）无论是否联合运动，在6个月随访时是否能显著改善6分钟步行距离。本研究调查了在TELEX试验中接受监督运动的人群中，TEL对肌肉细胞特征（肌纤维大小、卫星细胞含量、毛细血管密度、细胞外基质和胶原面积）和分子特征（细胞特异性转录组学）的探索性肌肉活检结果的影响。
从TELEX试验中13名患有PAD的参与者中获取基线和6个月随访时的肌肉活检样本，这些参与者被随机分为运动+TEL组（n = 6）或运动+PLA组（n = 7）。采用免疫组织化学法测量肌肉细胞特征，并用GeoMx数字空间分析系统对α-平滑肌肌动蛋白（α-SMA）阳性和α-SMA阴性细胞（主要是肌纤维）进行转录组分析。
与运动+PLA组相比，运动+TEL组平均肌纤维横截面积增加（+2175μm；95%置信区间，-266至4615；P = 0.04），与II型肌纤维相关的卫星细胞数量增加（+17；95%置信区间，-1至35；P = 0.03）。在α-SMA阴性细胞中，运动+TEL组上调了过氧化物酶体增殖物激活受体γ激活相关途径，包括一氧化氮-环磷酸鸟苷-蛋白激酶G信号通路（P = 0.008）和脂肪酸氧化（P = 0.011）。运动+TEL组相对于运动+PLA组在α-SMA阴性细胞中还降低了肌肉生长抑制素的表达（Log2倍数变化=-1.24；错误发现率=0.010）。
TEL可能通过降低肌肉生长抑制素表达、增加肌纤维大小以及增加过氧化物酶体增殖物激活受体γ的激活来影响运动对PAD患者肌肉的作用。需要进一步研究来证实这些发现。
