Deterioration of Limb Muscle Function during Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Abstract

Important features of both stable and acute exacerbation of chronic obstructive pulmonary disease (COPD) are skeletal muscle weakness and wasting. Limb muscle dysfunction during an exacerbation has been linked to various adverse outcomes, including prolonged hospitalization, readmission, and mortality. The contributing factors leading to muscle dysfunction are similar to those seen in stable COPD: disuse, nutrition/energy balance, hypercapnia, hypoxemia, electrolyte derangements, inflammation, and drugs (i.e., glucocorticoids). These factors may be the trigger for a downstream cascade of local inflammatory changes, pathway process alterations, and structural degradation. Ultimately, the clinical effects can be wide ranging and include reduced limb muscle strength. Current therapies, such as pulmonary/physical rehabilitation, have limited impact because of low participation rates. Recently, novel drugs have been developed in similar disorders, and learnings from these studies can be used as a foundation to facilitate discovery in patients hospitalized with a COPD exacerbation. Nevertheless, investigators should approach this patient population with knowledge of the limitations of each intervention. In this Concise Clinical Review, we provide an overview of acute muscle dysfunction in patients hospitalized with acute exacerbation of COPD and a strategic approach to drug development in this setting.

Keywords: COPD; drug development; exacerbations; pharmacological interventions; skeletal muscle.

Figure 1.

Schematic overview of anabolic and catabolic signaling in skeletal muscle. A number of underlying mechanisms contributing to imbalance between muscle protein synthesis and protein breakdown have been implicated in limb muscle mass loss in patients with chronic obstructive pulmonary disease (COPD) (, , –107). The ubiquitin proteasome pathway is a major driver of muscle proteolysis and includes the forkhead box O (FOXO) transcription factor–regulated muscle-specific E3 ubiquitin ligases muscle ring finger protein 1 E3-ligase (MuRF-1) and atrogin-1 (105, 108). The autophagy–lysosomal pathway is another contributing mechanism to protein degradation in response to atrophic stimuli in the setting of COPD (107). Conversely, the GH–IGF-1–AKT–mTOR axis positively affects protein synthesis and may attenuate protein breakdown via AKT-mediated negative regulation of FOXO. ActRIIB = activin receptor type IIB; AKT = protein kinase B; AR = androgen receptor; GH = growth hormone; GHR = growth hormone receptor; IGF-1 = insulin-like growth factor 1; IGF1R = insulin-like growth factor 1 receptor; IKK = IκB kinase; IR = insulin receptor; JAK2 = janus kinase 2; JNK = Jun N-terminal kinase; mTOR = mammalian target of rapamycin; MyoD = myogenic differentiation 1; NFκB = nuclear factor-κB; P38 = p38 mitogen-activated protein kinase; PI3K = phosphatidylinositol-4,5-bisphosphate 3-kinase; ROS = reactive oxygen species; STAT = signal transducer and activator of transcription.

Figure 2.

Factors and consequences in acute and chronic obstructive pulmonary disease (COPD)-related muscle dysfunction. The multiple factors related to muscle dysfunction in chronic and acute settings. Many of these factors are similar for both acute exacerbations of COPD and chronic stable COPD, with the notable exception of tobacco use and comorbidities (18, 21, 43, 54, 109). The large white arrows denote the direction of the impact. *Different muscle compartments show variable levels of cytokines. ^†Level dependent on time frame of illness. IGF-1 = insulin-like growth factor-1.