The mechanisms of cachexia underlying muscle dysfunction in COPD

Abstract

Pulmonary cachexia is a prevalent, debilitating, and well-recognized feature of COPD associated with increased mortality and loss of peripheral and respiratory muscle function. The exact cause and underlying mechanisms of cachexia in COPD are still poorly understood. Increasing evidence, however, shows that pathological changes in intracellular mechanisms of muscle mass maintenance (i.e., protein turnover and myonuclear turnover) are likely involved. Potential factors triggering alterations in these mechanisms in COPD include oxidative stress, myostatin, and inflammation. In addition to muscle wasting, peripheral muscle in COPD is characterized by a fiber-type shift toward a more type II, glycolytic phenotype and an impaired oxidative capacity (collectively referred to as an impaired oxidative phenotype). Atrophied diaphragm muscle in COPD, however, displays an enhanced oxidative phenotype. Interestingly, intrinsic abnormalities in (lower limb) peripheral muscle seem more pronounced in either cachectic patients or weight loss-susceptible emphysema patients, suggesting that muscle wasting and intrinsic changes in peripheral muscle's oxidative phenotype are somehow intertwined. In this manuscript, we will review alterations in mechanisms of muscle mass maintenance in COPD and discuss the involvement of oxidative stress, inflammation, and myostatin as potential triggers of cachexia. Moreover, we postulate that an impaired muscle oxidative phenotype in COPD can accelerate the process of cachexia, as it renders muscle in COPD less energy efficient, thereby contributing to an energy deficit and weight loss when not dietary compensated. Furthermore, loss of peripheral muscle oxidative phenotype may increase the muscle's susceptibility to inflammation- and oxidative stress-induced muscle damage and wasting.

Antagonistic implications of sarcopenia and abdominal obesity on physical performance in COPD

“…The higher prevalence of sarcopenia in COPD than in the healthy elderly (based on available literature [10]) reflects the suggested accelerated ageing in COPD, which is further supported by the reported shorter telomere length in COPD patients [18]. Potential catabolic triggers for inducing the sarcopenic process in COPD include physical inactivity, oxidative stress, inflammation, use of glucocorticosteroids and hypoxia [19]. As described in the recently published ERS statement on nutritional assessment and therapy in COPD [6], abnormally low FFMI in normal-to-underweight COPD patients is based on well-established adverse effects of low FFMI on physical performance and survival, and defined as a FFMI below age-and sex-specific 10th-percentile values.…”

Ascorbate infusion increases skeletal muscle fatigue resistance in patients with chronic obstructive pulmonary disease

“…free radicals; peripheral fatigue; ascorbate SKELETAL MUSCLE DYSFUNCTION plays a prominent role in limiting exercise and activities of daily living in patients with chronic obstructive pulmonary disease (COPD) (21,22). Numerous factors, including inactivity and skeletal muscle detraining (34), mitochondrial dysfunction (9), and oxidative stress (30) have all been implicated in the skeletal muscle dysfunction associated with COPD. Of these factors, the contribution of oxidative stress to reduced exercise capacity in patients with COPD has been well documented (11,13,24).…”

Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective

“…Doucet et al . compared the ratio of quadriceps to diaphragm AKT activation in COPD patients with controls and found a lower ratio in COPD 20. This implicates that the AKT activation is relatively higher in the diaphragm than in the quadriceps.…”

“…Furthermore, a shift in muscle fibre composition from type I (oxidative) to type II (glycolytic), accompanied by a decrease in oxidative capacity, culminates in reduced muscle endurance 18. This not only contributes to reduced exercise capacity19 but may also affect muscle mass in COPD,20 because type I and II fibres display different responses to anabolic and catabolic signals 21, 22…”