Skeletal muscle microcirculatory and mitochondrial function in patients with claudication and critical limb ischemia

Abstract

Introduction: Peripheral artery disease (PAD) is an atherosclerotic progressive disorder that impairs blood flow to the lower extremities. Early-stage patients often present with intermittent claudication (leg pain during walking, CLD), but as the disease progresses, patients can experience pain at rest and tissue death (critical limb ischemia, CLI). We recently reported that skeletal muscle microvascular endothelial dysfunction presented in claudicating patients with PAD. However, it is unknown if this microvascular dysfunction continues to progress with disease severity. Objective: To compare a direct investigation of the skeletal muscle microcirculation and the mitochondrial respiratory environment in patients with claudication and patients with CLI. Hypothesis: We hypothesize that (1) CLI will have greater attenuation in microcirculatory endothelial-dependent and endothelial-independent vasodilatory function (smooth muscle function) than CLD and (2) impairments in skeletal muscle microcirculatory vasodilatory function will contribute to attenuated mitochondrial respiratory function in CLD and CLI. Methods: Medial gastrocnemius muscles were harvested from PAD patients with CLD ( n = 5), CLI ( n = 6), and age-matched controls ( n = 6) by both muscle biopsies and open incisions. Arterioles were isolated to assess endothelium-dependent and independent vasodilatory responses to flow (30 mL·min -1 ), acetylcholine (ACh), and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiratory function was determined by high-resolution respirometry. Results: Endothelium-dependent vasodilation was attenuated ( P < 0.05) in response to flow (CON: 53.6 ± 23%, PAD: 26.7 ± 10.4%, CLI: 20.1 ± 14.5%) and ACh (10 -3 M, CON: 64 ± 6.9%, PAD: 39.1 ± 6.7%, CLI: 20.1 ± 14.5%) in both PAD and CLI compared to CON. However, endothelium-independent vasodilation with SNP was not different in any condition ( P > 0.05). Complex I+II state 3 mitochondrial respiration was blunted in both CLD and CLI compared to CON ( P < 0.05). However, state 4 respiration in CON was greater than CLI ( P < 0.05) but lower than CLD. Additionally, complex I+II state 3 respiration was positively associated with both flow ( r = 0.5, P = 0.01) and ACh mediated vasodilation ( r = 0.6, P = 0.009). No differences were found between CLD and CLI conditions. Conclusions: This was the first the first study to directly examine and compare skeletal muscle microvascular function in PAD patients with CLD and CLI. Our initial data indicate that functional characteristics of the skeletal muscle microvasculature and mitochondria are altered in PAD and deteriorate with disease progression. There is a correlation between alterations in the endothelium-dependent microvessel function and the dysfunction of mitochondria in the ischemic muscle raising the possibility that the microvascular dysfunction in PAD is produced by defects in the mitochondria of the microvascular endothelium. National Institutes of Health (R01 AG034995, R01 AG049868) NIH National Institute of General Medical Sciences, which funds the Great Plains IdeA-CTR Network (U54 GM115458) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.