Skeletal Muscle Mass and Quality in Peripheral Artery Disease: New Insights into Clinical Management and Therapeutic...

Peripheral artery disease (PAD) induces chronic limb ischemia that affects downstream skeletal muscle and leads to ischemic myopathy. Chronic ischemia results in mitochondrial dysfunction, oxidative stress, fiber-type shift, proteolysis, and anabolic resistance, contributing to reduced endurance and persistent weakness despite revascularization.

This narrative review provides a clinically oriented synthesis of PAD-related muscle pathology, pragmatic approaches to assessing muscle mass and quality, and current strategies to preserve or restore muscle health.

Chronic ischemia impairs mitochondrial biogenesis, increases reactive oxygen species, activates ubiquitin-proteasome and autophagy-lysosome pathways, and suppresses IGF-1/Akt/mTOR signaling, resulting in muscle atrophy and qualitative degeneration. Endothelial dysfunction and pro-inflammatory macrophage polarization further limit regeneration. Assessment begins with the ankle-brachial index and functional screening, followed by segmental bioimpedance or bedside ultrasound, with selective computed tomography or magnetic resonance imaging. Although exercise improves walking performance, endurance-only programs may inadequately preserve limb muscle, whereas resistance-inclusive training better maintains muscle mass and quality. Revascularization restores perfusion and mitigates ischemia, thereby preparing a physiological environment that supports, but does not by itself ensure, rehabilitation-driven improvements in skeletal muscle and functional recovery. Conventional PAD drugs reduce vascular risk but show limited direct muscle effects; mechanism-based therapies remain investigational.

Recognizing skeletal muscle as a therapeutic target supports an integrated management approach combining revascularization, resistance-inclusive exercise, nutritional optimization, and emerging muscle-directed therapies to improve mobility and clinical outcomes.