I am leading a research group at the Department of Physiology and Pharmacology at Karolinska Institutet. Here we aim to elucidate molecular pathological mechanisms of myopathy induced by peripheral artery disease (PAD). Comorbidities of type II diabetes (T2D) are major health concerns worldwide, including PAD. The prevalence of PAD is three to four times higher and severe in diabetic individuals compared with nondiabetic individuals and is a major cause of nonhealing ulcers, lower limb amputation and mortality. PAD lowers blood flow to the lower limb, causing muscle ischemia and dysfunction and reduced exercise tolerance, which can ultimately lead to tissue necrosis1. Interventions that improve distal arterial pressures (ie. bypass surgery or endovascular procedures) generally fail to normalise the structural and functional abnormalities of muscles, which point towards pathophysiological mechanisms inside the skeletal myofibers that reduce overall muscle function. However, despite serious muscle abnormalities, the field is lacking molecular understanding of PAD-induced muscle dysfunction. Moreover, research into type II diabetes and PAD often uses muscle tissue from the same patients as intraindividual controls. Given the systemic nature of the disease, this methodology may confound resulting data. This project will use state-of-the-art single nuclei sequencing (snSEQ), to characterise PAD myopathology. The affected ischemic muscles (distal of the occlusion) and ´non-ischemic´ muscles (proximal of the occlusion) will be compared to healthy control tissue from subjects with no history of T2D or PAD. Initial data from these analyses show that there is significant fibre atrophy, fat accumulation, fibrosis, and centralised myonuclei in both ischemic and non-ischemic tissues of PAD patients compared to healthy controls. This indicates that even muscle not directly affected by ischemia can exhibit significant abnormalities. By performing these in-depth analyses, we aim to create a gold-standard set of data that can be used to elucidate pathways that underlie the disease process. Next step is to perform comprehensive cellular analyses with snSEQ and the top candidate pathways will be selected for in vivo analysis in mouse models of PAD. The expected results will provide more specific mechanistic insight into the disease myopathology.