Background: Chronic limb threatening ischemia (CLTI) is the most severe form of the atherosclerotic peripheral arterial disease (PAD). Surgical interventions to restore blood flow are the primary treatments for CLTI, however failure rates of these interventions exceed 40%, indicating CLTI involves pathological changes to non-vascular cell types. Skeletal muscle quality and function is a strong predictor of morbidity and mortality among these patients. The replacement of skeletal muscle with intramuscular adipose tissue (IMAT) is prominent among patients with CLTI and is likely formed by differentiation of the muscle resident fibro-adipogenic progenitor cells (FAPs) into adipocytes. However, the impact of IMAT on limb function in CLTI remains unclear. Methods: To define the role of IMAT in CLTI, we used inducible FAP-specific Pparγ knockout mice (PparγFAP-KO) to inhibit IMAT formation. Cre-negative (Pparγfl/fl) littermates served as controls. Twelve-week-old male and female mice underwent femoral artery ligation (FAL) to induce hindlimb ischemia. Resting paw perfusion was measured using laser Doppler imaging. A nerve mediated 6-min limb function test involving repetitive submaximal isotonic contractions and laser Doppler flowmetry was used to measure muscular performance and perfusion in the gastrocnemius. Levels of IMAT, muscle size and capillary densities were assessed histologically. Results: FAP-specific deletion of Pparγ repressed IMAT formation following FAL (p< 0.01). PparγFAP-KO mice had larger muscle fiber cross-sectional area and improved muscle function compared to Pparγfl/fl controls in both sexes. No differences were observed in resting paw perfusion, yet in the gastrocnemius, female PparγFAP-KO mice had greater contraction-induced hyperemia and perfused capillary densities compared to controls. Linear regression analysis revealed a significant inverse relationship between IMAT and muscle strength (p< 0.0001), suggesting that IMAT formation compromises muscle function in CLTI. Conclusions: These findings demonstrate that pathological IMAT deposition derived from FAPs directly worsens limb function in preclinical CLTI models and demonstrates that limiting IMAT develop in the ischemic limb improves function. 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.
Palzkill et al. (Fri,) studied this question.