Muscle Mitochondrial Dysfunction in COPD: Beyond Oxygen Consumption

Abstract

In the June issue of Acta Physiologica, Abdellaoui and colleagues provide a detailed examination of skeletal muscle mitochondrial dysfunction in patients with chronic obstructive pulmonary disease (COPD) and its central and peripheral physiological adaptations to endurance training [1]. COPD is a leading cause of morbidity and mortality worldwide, accompanied by a high economic burden and years of disability, both projected to increase to 2050 [2]. Skeletal muscle represents approximately 50% of body weight and represents a potent target for interventions for extra-pulmonary manifestations of COPD, such as sarcopenia, osteopenia, metabolic syndrome, and hypertension [3]. Thus, understanding the adaptations induced by COPD to skeletal muscle is key to investigating the potential moderating effects of these extrapulmonary manifestations. However, direct measurements of skeletal muscle mitochondrial function in humans with chronic diseases are scarce, and reports of its changes after exercise interventions are limited. Abdellaoui and colleagues demonstrate that COPD has a lower ATP synthesis rate (Figure 1A), lower oxidative phosphorylation (OXPHOS) efficiency (ATP/O ratio; Figure 1B), increased lipid peroxidation production, and higher resting proton leak (Figure 1C) compared to sedentary healthy individuals. Their research underscores the critical role of mitochondria in the pathophysiology of COPD, as matching individuals by physical activity levels allows for the exclusion of the effect of disuse on muscle function and shows that specific traits of COPD (chronic inflammation or oxidative stress) have a direct impact on mitochondrial function. This may explain the previous inverse association found between systemic inflammation (tumor necrosis factor-alpha) and maximal aerobic capacity (i.e., VO_2max) in patients with moderate COPD [4].

The findings by Abdellaoui and colleagues bridge a gap in understanding how peripheral limitations beyond ventilatory constraints, such as mitochondrial function, contribute to exercise intolerance in COPD patients. Interestingly, the decreased maximal respiration rates with substrates like palmitoyl-carnitine and pyruvate, as well as mitochondrial complexes expression in skeletal muscle, were not rescued by endurance training (ET) in COPD. However, ET enhanced ATP synthesis rates and downregulated uncoupled respiration in COPD patients, which was not evidenced in maximal oxygen consumption (VO_2max; table 2), consistent with previous studies [5, 6]. This highlights the importance of investigating muscle mitochondrial changes beyond the VO_2max adaptations in patients with COPD. Additionally, the authors reported that mitochondrial lipid peroxidation decreased after ET in patients with COPD only, while mitochondrial protein carbonylation remained unaltered in both groups. Interestingly, mitochondrial superoxide dismutase (MnSOD) expression increased after ET in healthy individuals but not in COPD patients, suggesting a blunted mitochondrial antioxidant enzyme adaptation despite reductions in lipid peroxidation. Together, these findings indicate that although ET can partially restore mitochondrial oxidative balance in the skeletal muscle of patients with COPD, disease-specific limitations in antioxidant adaptability may restrict the full recovery of mitochondrial function, reinforcing the need for complementary interventions to optimize skeletal muscle health in this population.

The article opens several avenues for future research in COPD. First, the limited skeletal muscle mitochondrial adaptations to exercise training in patients with COPD suggest a need to explore alternative interventions to enhance mitochondrial content and function (i.e., number, volume, and oxidative capacity). Given that mitochondria are central regulators of skeletal muscle metabolism, coordinating oxidative phosphorylation, ATP production, substrate utilization, and redox balance, preserving their bioenergetic efficiency is essential for muscle protein synthesis and function in COPD. Impairments in these processes compromise both muscle preservation (or wasting) and energy expenditure during physical activity, which are key determinants of exercise tolerance in COPD.

Understanding muscle dysfunction and the effects of exercise training on these impairments will enable the design of more effective exercise interventions to improve the quality of life for patients with COPD. Hence, as the global burden of COPD continues to rise, studies on the underlying physiological mechanisms are equally important and warranted.

The authors declare no conflicts of interest.