Telmisartan modulates exercise responses in peripheral artery disease: Analyses of skeletal muscle from the TELEX Trial

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Objective 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. Methods 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). Results Compared with exercise + PLA, exercise + TEL increased mean myofiber cross-sectional area (+2175 μm 2 ; 95% confidence interval, −266 to 4615; P = .04) and the number of satellite cells associated with type II myofibers (+17; 95% confidence interval, −1 to 35; P = .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 ( P = .008), and fatty acid oxidation ( P = .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). Conclusions 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.

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