Exercise-induced Myokines and Muscle–Vascular Crosstalk in Peripheral Artery Disease Management: From Bench to Practice

Abstract Peripheral artery disease (PAD) significantly limits walking capacity and impairs quality of life. Although structured exercise therapy is recommended for symptomatic PAD, its clinical benefit appears paradoxical, as exercise does not reduce plaque burden or reverse large-vessel arterial obstruction and is often limited by exertional leg pain. Instead, repeated skeletal muscle contraction induces microvascular dilation, collateral recruitment, and improved muscle oxygen utilization, providing functional benefits independent of changes in arterial stenosis. Preclinical and translational evidence indicates that contracting skeletal muscle acts as an endocrine organ, releasing myokines that mediate muscle–vascular communication. Among these mediators, follistatin-like 1 (FSTL1) has been implicated in endothelial repair, nitric oxide signaling, and vascular adaptation. Through this muscle–vascular crosstalk, exercise produces improvements in functional performance despite persistent vascular stenosis. This review synthesizes mechanistic and clinical evidence to address the gap between exercise as a behavioral recommendation and exercise as a biologically active, disease-modifying intervention in PAD. By integrating myokine signaling, microcirculatory adaptation, and functional outcomes, we link mechanistic insights to evidence-based exercise prescriptions aligned with contemporary guideline recommendations, and identify directions for future translational and clinical research.