Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting

Abstract

Chronic obstructive pulmonary disease (COPD) is a worldwide prevalent respiratory disease mainly caused by tobacco smoke exposure. COPD is now considered as a systemic disease with several comorbidities. Among them, skeletal muscle dysfunction affects around 20% of COPD patients and is associated with higher morbidity and mortality. Although the histological alterations are well characterized, including myofiber atrophy, a decreased proportion of slow-twitch myofibers, and a decreased capillarization and oxidative phosphorylation capacity, the molecular basis for muscle atrophy is complex and remains partly unknown. Major difficulties lie in patient heterogeneity, accessing patients' samples, and complex multifactorial process including extrinsic mechanisms, such as tobacco smoke or disuse, and intrinsic mechanisms, such as oxidative stress, hypoxia, or systemic inflammation. Muscle wasting is also a highly dynamic process whose investigation is hampered by the differential protein regulation according to the stage of atrophy. In this review, we report and discuss recent data regarding the molecular alterations in COPD leading to impaired muscle mass, including inflammation, hypoxia and hypercapnia, mitochondrial dysfunction, diverse metabolic changes such as oxidative and nitrosative stress and genetic and epigenetic modifications, all leading to an impaired anabolic/catabolic balance in the myocyte. We recapitulate data concerning skeletal muscle dysfunction obtained in the different rodent models of COPD. Finally, we propose several pathways that should be investigated in COPD skeletal muscle dysfunction in the future.

Keywords: cachexia; interleukin; metabolism; myocyte.

Figure 1

Schematic representation of the main histopathological alterations in COPD skeletal muscle. Alterations of skeletal muscle tissue in COPD result from both extrinsic factors (malnutrition, tobacco exposure, deconditioning) and intrinsic factors (hormonal imbalance, oxidative stress, inflammation, hypoxia and hypercapnia, and genetic and epigenetic modifications). Created with BioRender.com (accessed on 1 February 2023).

Figure 2

Alteration of the hypertrophy/atrophy balance leading to impaired protein turnover in COPD myocytes. Anabolic (hypertrophic) processes are represented in blue and catabolic (atrophic) in red. The chosen pathways have been identified as dysregulated in COPD patients or experimental models of COPD. IFN, interferon. IGF, insulin growth factor. IL, interleukin. MAPK, mitogen-activated protein kinase. Created with BioRender.com (accessed on 1 February 2023).