Therapeutic prospects to treat skeletal muscle wasting in COPD (chronic obstructive lung disease)

Abstract

Chronic obstructive pulmonary disease (COPD) is an incurable group of lung diseases characterised by progressive airflow limitation and loss of lung function, which lead to profound disability. It is mostly caused by cigarette smoke. Although COPD is one of the most prevalent diseases worldwide and its incidence is increasing, current therapies do little to improve the condition. Much current research focuses on strategies to halt the accelerated rate of decline in lung function that occurs in the disease. However, as most symptoms occur when the lungs are already extensively and irreversibly damaged, it is uncertain whether an agent able to slow or halt decline in lung function would actually provide relief to COPD patients. As lung function worsens, systemic comorbidities contribute markedly to disability. Loss of lean body mass (skeletal muscle) has recently been identified as a major determinant of disability in COPD and an independent predictor of mortality. In contrast to lung structure damage, skeletal muscle retains regenerative capacity in COPD. In this review, we discuss mechanisms of wasting in COPD, focusing on therapeutic strategies that might improve the health and productive life expectancy of COPD patients by improving skeletal muscle mass and function. Single or combination approaches exploiting the suppression of procatabolic inflammatory mediators, inhibition of ubiquitin ligases, repletion of anabolic hormones and growth factors, inhibition of myoblast apoptosis, remediation of systemic oxidative stress and promotion of repair, and regeneration via stimulation of satellite cell differentiation hold considerable therapeutic promise.

Introduction

Worldwide, 600 million people are afflicted with chronic obstructive pulmonary disease (COPD), and it is predicted to become the third largest cause of death and fifth most common cause of disability in the world by 2020 (Lopez & Murray, 1998). Cigarette smoking is the major etiological factor for the development of COPD, with around 15–20% of long-term smokers developing the condition (Barnes et al., 2003). COPD is defined as “a disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases” (Pauwels & Rabe, 2004). The main symptoms of the disease are chronic cough, sputum production, and dyspnea (shortness of breath), particularly during exercise. Currently, no therapies exist to halt the inevitable progression of the disease, and this, together with the immense global disease burden, has prompted a rapid and intense growth in research interest in finding effective strategies to treat this disorder.

The severity of COPD is currently graded using the Global initiative on Obstructive Lung Disease (GOLD) criteria (www.goldcopd.com) based on a decline in the ratio of 2 simply measured lung spirometric parameters: the Forced Vital Capacity (the volume of air expired in a forced expiration measured from deep inspiration to full expiration) versus the forced expiratory volume in 1 sec (FEV; Table 1). Recently, alternative classifications, such as the BODE (body mass index, degree of airflow obstruction, dyspnea, and exercise tolerance) method, have also been described on the basis that COPD patients also have systemic manifestations of the disease that are not well reflected in spirometry (Celli et al., 2004). As lung function worsens, COPD is accompanied by increasing susceptibility to exacerbations. An acute exacerbation of COPD (AECOPD) is defined as “a sustained worsening of the patient's condition, from the stable state and beyond normal day to day variation, that is acute in onset and necessitates change in regular medication in a patient with underlying COPD” (Rodriguez-Roisin, 2000). AECOPD are a common cause of morbidity and mortality in COPD patients and place a large burden on health care resources (Seemungal et al., 1998). As lung function declines, that is, GOLD 2+, patients are at progressively increased risk of suffering infectious and other exacerbations.

It is currently believed that excessive inflammation induced by smoke exposure triggers the accelerated decline in lung function that eventually results in respiratory insufficiency, usually first noticed by patients as shortness of breath (dyspnea) on exertion. Accordingly, most research to date has focused on slowing or halting the progression of airflow limitation, by targeting inflammation which is thought to underlie emphysema, small airway thickening, and mucus hypersecretion. Inhaled anti-inflammatory glucocorticosteroids can produce a small but clinically meaningful improvement in basal lung function in some patients, but they exert no effect on the rate of decline. Similarly, anticholinergic and beta-2 adrenoceptor agonist bronchodilators do provide some symptomatic relief, even if changes in spirometry are unimpressive, but do not affect disease progression (Wouters, 2004). AECOPD are associated with intensification of inflammation.