Molecular and biological pathways of skeletal muscle dysfunction in chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD) will be a major leading cause of death worldwide in the near future. Weakness and atrophy of the quadriceps are associated with a significantly poorer prognosis and increased mortality in COPD. Despite that skeletal muscle dysfunction may affect both respiratory and limb muscle groups in COPD, the latter are frequently more severely affected. Therefore, muscle dysfunction in COPD is a common systemic manifestation that should be evaluated on routine basis in clinical settings. In the present review, several aspects of COPD muscle dysfunction are being reviewed, with special emphasis on the underlying biological mechanisms. Figures on the prevalence of COPD muscle dysfunction and the most relevant etiologic contributors are also provided. Despite that ongoing research will shed light into the contribution of additional mechanisms to COPD muscle dysfunction, current knowledge points toward the involvement of a wide spectrum of cellular and molecular events that are differentially expressed in respiratory and limb muscles. Such mechanisms are thoroughly described in the article. The contribution of epigenetic events on COPD muscle dysfunction is also reviewed. We conclude that in view of the latest discoveries, from now, on new avenues of research should be designed to specifically target cellular mechanisms and pathways that impair muscle mass and function in COPD using pharmacological strategies and/or exercise training modalities.

Keywords: COPD; epidemics; molecular and cellular events; muscle adaptation; muscle atrophy; respiratory and peripheral muscle dysfunction.

Figure 1.

Schematic representation of the most important differences between respiratory and peripheral muscle dysfunction in COPD patients. The mechanical factors, mainly characterized by alterations in thorax geometry and inspiratory overloads, play a paramount role in the ventilatory muscle dysfunction of these patients. COPD: chronic obstructive pulmonary disease.

Figure 2.

Schematic representation of the relevance of skeletal muscle dysfunction and exercise intolerance as factors that predict prognosis in patients with COPD. COPD: chronic obstructive pulmonary disease.

Figure 3.

Schematic representation on how the identified etiological factors (dark red panels) contribute to lower limb muscle dysfunction in COPD through the action of biological mechanisms (black panels) that negatively impact muscle phenotype and function in the patients. COPD: chronic obstructive pulmonary disease.

Figure 4.

Schematic representation on how the different etiological factors (dark red panels) contribute to respiratory muscle dysfunction in COPD through the action of several biological mechanisms (black panels) that modify muscle phenotype and function in the patients. Several etiological factors exert beneficial effects (training-like effect, green panel) on muscle mass and performance through the action of different biological mediators (adaptive muscle phenotype, right-hand side panels) that lead to a certain adaptation of the inspiratory muscles in COPD. These adaptive mechanisms partly counterbalance the deleterious effects of other factors and biological mechanisms (middle black panels). COPD: chronic obstructive pulmonary disease.

Figure 5.

Immunohistochemical staining using a specific antibody of type II fibers (dark brown) in the vastus lateralis of a COPD patient and a healthy control subject. Note that type II fibers were of smaller size in the muscles of the patients (for review see Puig-Vilanova et al., 2015). COPD: chronic obstructive pulmonary disease.

Figure 6.

Ultrastructural images of sarcomerae in the vastus lateralis of a COPD patient and a healthy control subject. Note that sarcomerae were significantly more disrupted in the muscles of the COPD (for review see Puig-Vilanova et al., 2015). COPD: chronic obstructive pulmonary disease.

Figure 7.

A representative example of TUNEL-positive nuclei (dark brown staining, black arrow) together with non-stained nuclei (blue, red arrow) in the vastus lateralis of a COPD patient. COPD: chronic obstructive pulmonary disease; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.

Figure 8.

Representative electron micrographs of early and late apoptotic nuclei as identified using electron microscopy in the vastus lateralis of a COPD patient. COPD: chronic obstructive pulmonary disease.

Figure 9.

Representative electron micrographs of autophagosomes (white arrows) as identified using electron microscopy in the vastus lateralis of a COPD patient and a healthy control subject. Note that the number of autophagosomes was greater in the muscles of the patient (for review see Puig-Vilanova et al., 2015). COPD: chronic obstructive pulmonary disease.

Figure 10.

Immunohistochemical staining using a specific antibody of type I fibers (dark brown) in the diaphragm of a COPD patient and a healthy control subject. COPD: chronic obstructive pulmonary disease.

Figure 11.

A representative example of TUNEL-positive nuclei (dark brown staining, black arrow) together with non-stained nuclei (blue, red arrow) in the diaphragm of a COPD patient. COPD: chronic obstructive pulmonary disease; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.