Muscle dysfunction often occurs in patients with chronic obstructive pulmonary disease (COPD) and may involve both respiratory and locomotor (peripheral) muscles. The loss of strength and/or endurance in the former can lead to ventilatory insufficiency, whereas in the latter it limits exercise capacity and activities of daily life. Muscle dysfunction is the consequence of complex interactions between local and systemic factors, frequently coexisting in COPD patients. Pulmonary hyperinflation along with the increase in work of breathing that occur in COPD appear as the main contributing factors to respiratory muscle dysfunction. By contrast, deconditioning seems to play a key role in peripheral muscle dysfunction. However, additional systemic factors, including tobacco smoking, systemic inflammation, exercise, exacerbations, nutritional and gas exchange abnormalities, anabolic insufficiency, comorbidities and drugs, can also influence the function of both respiratory and peripheral muscles, by inducing modifications in their local microenvironment. Under all these circumstances, protein metabolism imbalance, oxidative stress, inflammatory events, as well as muscle injury may occur, determining the final structure and modulating the function of different muscle groups. Respiratory muscles show signs of injury as well as an increase in several elements involved in aerobic metabolism (proportion of type I fibers, capillary density, and aerobic enzyme activity) whereas limb muscles exhibit a loss of the same elements, injury, and a reduction in fiber size. In the present review we examine the current state of the art of the pathophysiology of muscle dysfunction in COPD.

Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings

Although adenocarcinoma (ADC) is the most frequent lung cancer, its diagnosis is often late, when the local invasion is important and/or the metastases have already appeared. Therefore, the mortality at 5 years is still very high, ranging from 51% to 99%, depending on the stage. The implementation of different molecular techniques has allowed genomic studies even in relatively small histological samples such as obtained with non-invasive or minimally invasive techniques, facilitating a better phenotyping of lung ADC. Thus, current classification differentiates between preinvasive lesions (atypical adenomatous hyperplasia and in situ ADC), minimally invasive ADC (MIA) and invasive ADC. 'Field cancerization' is a concept that refers to progressive loco-regional changes occurring in tissues exposed to carcinogens, due to the interaction of the latter with a predisposing genetic background and an appropriate tissue microenvironment. Somatic genetic alterations, including mutations but also other changes, are necessary for oncogenesis, being especially frequent in lung ADC. Changes in the epidermal growth factor receptor (EGFR) gene, Kirsten rat sarcoma viral oncogene (KRAS), v-Raf murine sarcoma viral oncogene homolog B (BRAF), gene encoding neurofibromin (NF1), anaplastic lymphoma kinase (ALK) and ROS1 are the main genes that suffer alterations in the tumors of patients with ADC. Molecular profiling of these tumors allows more targeted treatments through two distinct strategies, genome-guided therapy and immunotherapy. The former, targets the aberrant pathways secondary to the genomic alteration, whereas the latter may be based on the administration of antibodies [such as those against cytotoxic T-lymphocyte antigen 4 (CTLA-4) or the programmed cell death ligand 1/protein 1 pathway (PD-L1/PD-1)] or the stimulation of the patient's own immune system to produce a specific response. These strategies are obtaining better results in selected ADC patients.

Nutritional abnormalities are frequent in different chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF), interstitial fibrosis and lung cancer, having important clinical consequences. However, nutritional abnormalities often remained underdiagnosed due to the relative lack of awareness of health professionals. Therefore, systematic anthropometry or even better, assessment of body composition, should be performed in all patients with chronic respiratory conditions, especially following exacerbation periods when malnutrition becomes more accentuated. Nutritional abnormalities very often include the loss of muscle mass, which is an important factor for the occurrence of muscle dysfunction. The latter can be easily detected with the specific assessment of muscle strength and endurance, and also negatively influences patients’ quality of life and prognosis. Both nutritional abnormalities and muscle dysfunction result from the interaction of several factors, including tobacco smoking, low physical activity-sedentarism, systemic inflammation and the imbalance between energy supply and requirements, which essentially lead to a negative balance between protein breakdown and synthesis. Therapeutic approaches include improvements in lifestyle, nutritional supplementation and training. Anabolic drugs may be administered in some cases.

Many respiratory diseases lead to impaired function of skeletal muscles, influencing quality of life and patient survival. Dysfunction of both respiratory and limb muscles in chronic obstructive pulmonary disease has been studied in depth, and seems to be caused by the complex interaction of general (inflammation, impaired gas exchange, malnutrition, comorbidity, drugs) and local factors (changes in respiratory mechanics and muscle activity, and molecular events). Some of these factors are also present in cystic fibrosis and asthma. In obstructive sleep apnea syndrome, repeated exposure to hypoxia and the absence of reparative rest are believed to be the main causes of muscle dysfunction. Deconditioning appears to be crucial for the functional impairment observed in scoliosis. Finally, cachexia seems to be the main mechanism of muscle dysfunction in advanced lung cancer. A multidimensional therapeutic approach is recommended, including pulmonary rehabilitation, an adequate level of physical activity, ventilatory support and nutritional interventions.

The respiratory microbiome is altered in COPD patients but its relationship with core components of the disease, such as the severity of airflow limitation, the frequency of exacerbations or the circulating levels of eosinophils, is unclear. Cross-sectional study comprising 72 clinically stable COPD patients (mean age 68 [SD 7.9] years; FEV1 48.7 [SD 20.1]% of reference) who provided spontaneous sputum samples for 16S rRNA gene amplification and sequencing. The microbiome composition was analysed with QIIME. We observed that: (1) more severe airflow limitation was associated with reduced relative abundance (RA) of Treponema and an increase in Pseudomonas; (2) patients with ≥2 exacerbations the previous year showed a significantly different bacterial community with respect to non-exacerbators (p = 0.014), with changes in 13 genera, including an increase of Pseudomonas, and finally, (3) peripheral eosinophils levels ≥2% were associated with more diverse microbiome [Chao1 224.51 (74.88) vs 277.39 (78.92) p = 0.006; Shannon 3.94 (1.05) vs 4.54 (1.06) p = 0.020], and a significant increase in the RAs of 20 genera. The respiratory microbiome in clinically stable COPD patients varies significantly according to the severity of airflow limitation, previous history of exacerbations and circulating eosinophils levels.