Introduction: Cilostazol is a phosphodiesterase 3 (PDE3) inhibitor and one of the only approved medications shown to improve walking performance in patients with peripheral artery disease (PAD). However, its effects on skeletal muscle pathophysiology are poorly understood. Because skeletal muscle dysfunction contributes to mobility impairment in PAD, this study examined whether cilostazol use was associated with differences in skeletal muscle structure, mitochondrial function, or gene expression. Methods: We conducted a cross-sectional analysis of 50 patients with PAD, including 15 taking cilostazol and 35 not taking the medication. Calf muscle strength was measured using isometric dynamometry. Gastrocnemius muscle biopsies were analyzed for myofiber morphology, mitochondrial respiration using high-resolution respirometry, and gene expression through RNA sequencing. Results: Calf muscle strength (P=0.49), myofiber cross-sectional area (Type I: P=0.53; Type IIa: P=0.59), and capillary density (P=0.74) did not differ between groups. However, mitochondrial oxygen consumption under physiological energy demand was significantly higher in cilostazol-treated patients (P=0.0137), while oxidative phosphorylation conductance (P=0.37) and mitochondrial hydrogen peroxide emission remained unchanged. RNA sequencing showed overall transcriptomic similarity, but gene set enrichment analysis revealed upregulation of mitochondrial gene expression pathways and downregulation of inflammatory signaling in cilostazol users. Conclusion: Cilostazol use in patients with PAD is associated with higher mitochondrial oxygen consumption and modest transcriptomic changes but did not result in differences in muscle strength, myofiber size, or capillarization. These findings suggest limited structural effects of cilostazol on skeletal muscle, while potential metabolic benefits warrant further investigation. Sources of Funding: This study was supported by National Institutes of Health (NIH) grants R01-HL149704 and HL171050 (T.E.R.) and the American Heart Association grant 25EIA1369187 (T.E.R.). S.T.S. was supported by NIH grant R01-HL148597. S.A.B. was supported by NIH grant R01-DK119274. K.K. was supported by the American Heart Association grant POST903198. T.T. was supported by NIH grant F31-DK128920. V.R.P. was supported by NIH grant F31-HL174156 and the American Heart Association grant 24PRE1193999. C.G.P. was supported by the American Heart Association grant 24PRE1196311 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Jaewon Choi (2026) studied this question.