Abstract Body: Peripheral artery disease (PAD) is caused by prolonged atherosclerosis which results in pain and numbness of extremities, muscle atrophy, and potential amputation in severe cases. Despite exercise being an effective method to combat early-stage PAD, the primary effective treatment for mid-late-stage PAD is revascularization surgery; however, this surgery often fails to prevent disease progression and reduce rate of amputation and mortality. To explore the mechanisms and potential interventions for PAD, BALB/c mice were subjected to femoral artery ligation of the hindlimb, simulating pathological manifestations found in PAD patients. Using laser doppler imaging, we confirmed that mice with femoral artery ligation had significantly lower blood flow to the affected hindlimb compared to the control limb (p<0.05). Histology was used to visualize centrally located nuclei and collagen deposition at 1, 3, 6, and 12 weeks after ligation, depicting muscle damage and fibrosis. Furthermore, immunostaining of muscle fibers showed significantly decreased cross sectional area 6 weeks after ligation (p<0.05), representing increased muscle atrophy. In situ testing showed that ischemic muscle had significantly decreased muscle contractile force and endplate potential (p<0.05). Consistent with these results, immunostaining of the neuromuscular junction (NMJ) showed increased denervation and fragmentation of nicotinic acetylcholine receptor clusters. Additionally, western blot showed significantly decreased expression of Rapsyn (p<0.05), an essential scaffolding protein at the NMJ. Interestingly, western blot also showed that macrophage colony-stimulating factor (M-CSF), a promotor of macrophage proliferation and activation, was significantly upregulated beginning 3 weeks after ligation (p<0.05). Moreover, protein expression of pan macrophage marker CD68 was significantly increased beginning 1 week after ligation, and NFκB P65, a pro-inflammatory signaling protein, was significantly upregulated in ischemic muscle (p<0.05) 12 weeks after ligation. This data suggests that muscle atrophy and NMJ damage in PAD may be associated with chronic pro-inflammatory-related signaling pathways via continuous expression of M-CSF.