Abstract Body: Introduction: Skeletal muscle health and function are critical determinants of clinical outcomes in peripheral arterial disease (PAD). Unfortunately, the mechanism that governs failed muscle regeneration in PAD patients remains largely unresolved.

Methods & Results: We explored the transcriptomes of skeletal muscle biopsies from 51 patients (non-PAD, n = 15; intermittent claudication, n = 20; and CLTI, n = 16). These data demonstrated a senescence transcriptional signature in CLTI patients. Next, we performed hindlimb ischemia (HLI) and sham surgery on C57BL/6 mice (age 10-12 weeks) and FACS-isolated senescent cells. Our FACS method was based on the fluorescent probe SPiDER-ß-gal (SPiDER). We demonstrated that senescent cells accumulated in the ischemic limb compared to the sham-surgery limb. Next, we wished to determine if cellular senescence was associated with other histological hallmarks of CLTI, such as impaired muscle regeneration and adipogenesis. Hence, we performed HLI on C57BL/6 and BALB/c mice; BALB/c mice recapitulate the human CLTI phenotype. These data show that senescent cells are enriched in the BALB/c limb compared to C57BL/6 limb.

Conclusions: Collectively, these data demonstrate that cellular senescence is a signature of the ischemic limb.