Increased skeletal muscle mitochondrial free radical production in peripheral arterial disease despite preserved mitochondrial respiratory capacity

Abstract

Skeletal muscle mitochondrial dysfunction, which is not fully explained by disease-related arterial occlusion, has been implicated in the pathophysiology of peripheral arterial disease (PAD). Therefore, this study comprehensively assessed mitochondrial respiratory function in biopsies from the gastrocnemius of 10 patients with PAD (Fontaine Stage II) and 12 healthy controls (HC). Intramuscular and systemic inflammation, mitochondria-derived reactive oxygen species (ROS) production, and oxidative stress were also assessed to better understand the mechanisms responsible for the proposed PAD-induced mitochondrial dysfunction. Interestingly, mitochondrial respiratory capacity, assessed as complex I (CI) and complex II (CII)-driven State 3 respiration, measured separately and in combination (State 3 CI+II), revealed no difference between the patients with PAD and the HC. However, mitochondria-derived ROS production was significantly elevated in PAD (HC: 1.0 ± 0.9; PAD: 4.3 ± 1.0 AU (mg tissue) ). Furthermore, patients with PAD exhibited significantly greater concentrations of the pro-inflammatory markers tumour necrosis factor α in plasma (HC: 0.9 ± 0.4; PAD: 2.0 ± 0.3 pg ml ) and interleukin 6 in both plasma (HC: 2.3 ± 0.4; PAD: 4.3 ± 0.5 pg ml ) and muscle (∼75% greater). Intramuscular oxidative stress, assessed by protein carbonyls and 4-hydroxynonenal, was significantly greater in PAD compared to HC. Ankle brachial index was significantly correlated with intramuscular inflammation, oxidative stress and mitochondria-derived ROS production. Thus, elevated intramuscular inflammation, oxidative stress and mitochondria-derived ROS production are likely to contribute to the pathophysiology of the skeletal muscle dysfunction associated with PAD, even in the presence of preserved mitochondrial respiratory function in this population.

The Rise of Mitochondria in Peripheral Arterial Disease Physiopathology: Experimental and Clinical Data

“…Similar to the findings on experimental models, PAD patients displayed increased mitochondria-derived ROS production characterized by elevated levels of free radical species [32].…”

“…Oxygraphy measurements in PAD patients revealed significantly altered respiratory activity, notably of complexes I, III and IV, and of the acceptor control ratio [27][28][29][30]. Interestingly, more recent studies reported no difference in the mitochondrial respiration rate between PAD patients and healthy controls, despite alterations in O 2 delivery, tissue-reoxygenation and ATP synthesis rate during exercise [31,32]. These conflicting findings could be explained by disparities in disease severity.…”

High‐intensity exercise training ameliorates aberrant expression of markers of mitochondrial turnover but not oxidative damage in skeletal muscle of men with essential hypertension

“…In support of this, endothelium‐derived NO is thought not only to modulate vascular tone but also to regulate skeletal muscle mitochondrial turnover, suggesting that impairments in NO bioavailability may negatively impact muscle mitochondrial quality and vice versa. Furthermore, increased mitochondrial ROS production and oxidative damage have been recently observed in skeletal muscle from patients with peripheral arterial disease, a vascular disorder often associated with hypertension.…”

Sarcopenia and peripheral arterial disease: a systematic review

“…45 PAD was also associated with significant oxidative stress and ROS production. 46 Interestingly, the extend of oxidative damage in PAD gastrocnemius was shown to be associated with advanced disease stage and lower myofibre cross-sectional area. 47 Taken together, these data suggest the pathological implication of excessive oxidative stress in myofibres damage and PAD.…”