© 2002 American Thoracic Society
Apoptosis as a Potential Mechanism of Muscle Cachexia in Chronic Obstructive Pulmonary DiseaseDivision of Pulmonary/Critical Care Medicine Burns & Allen Research Institute Cedars-Sinai Medical Center School of Medicine University of California at Los Angeles Los Angeles, California There is mounting evidence that limb muscle dysfunction and/or muscle wasting is common in patients with chronic obstructive pulmonary disease (COPD) and may contribute to morbidity, including exercise intolerance (1). Possible mechanisms include the adverse effects of nutritional depletion (a quarter to a third of ambulatory patients), use of corticosteroids, deconditioning, reduced serum insulin-like growth factor-1 and testosterone levels, chronic hypoxemia, and elaboration of inflammatory mediators (1). In this issue of AJRCCM (pp. 485–489), Agustí and coworkers provide data suggesting that apoptotic pathways may be involved in skeletal muscle atrophy in patients with COPD (2). Apoptosis or programmed cell death is a regulated physiologic process critical to cellular homeostasis, which can become dysregulated, leading to disease states including muscle disease or dysfunction (3). Apoptosis results in cell shrinkage, DNA fragmentation, membrane blebbing, and disassembly into apoptotic bodies (membrane-bound cell fragments). These bodies are eliminated by phagocytic cells without spillage of cell contents or induction of an inflammatory response (see Figure E1 on apoptotic signaling pathways in the online data supplement). Agustí and coworkers (2) report a high percentage of apoptotic myonuclei in vastus lateralis muscle biopsies of patients with COPD, using a transferase-mediated dUTP biotin nick end labeling assay to label DNA fragments. In patients with body mass indices (BMI) greater than 20 kg/m2, the percentage of apoptotic myonuclei was 17.1 ± 4.2%, whereas in patients with BMI less than 20 kg/m2, it increased to 57.1 ± 12.4%. In contrast, in healthy or inactive control subjects, the percentage of apoptotic nuclei was 3.8 ± 1.8 and 6.0 ± 2.3%, respectively. A similar trend was noted using Western blotting to assay cleaved poly(adenosine 5' diphosphate-ribose) polymerase, a protein normally involved in DNA repair, as a marker of cells undergoing apoptosis. How can we link apoptosis of muscle nuclei with muscle fiber atrophy? Central to this is the concept of myonuclear domain size (4). It is generally accepted that there is a finite ratio between both the size (myoplasmic volume) of a muscle fiber and the number of myonuclei within a given fiber with the volume per myonucleus (designated the myonuclear domain size). Each myonucleus regulates protein expression within a given myoplasmic volume. Thus, the loss of myonuclei through apoptotic or other mechanisms would be expected to result in fiber atrophy to maintain myonuclear domain size in the remodeling process (4).
Another fundamental question pertinent to the paper by Agustí and coworkers (2) is, what mechanisms are responsible for inducing apoptosis of myonuclei in limb muscles of patients with COPD? Further understanding of the apoptotic signaling pathways in muscle provides a framework based on which certain postulates may be advanced (see Figure E1 in the online data supplement to this editorial). The two principal signaling pathways of apoptosis are mediated either through the death receptor or through mitochondrial pathways (5). Death receptors include tumor necrosis factor receptor-1, Fas, and others, which together with their specific ligands recruit specialized adapter proteins to activate caspases (cysteine proteases) that are key regulators of apoptosis. It is interesting, therefore, that a chronic inflammatory process present in the airways of patients with COPD has recently been highlighted (6). Furthermore, circulating levels of tumor necrosis factor- Mitochondrial pathways also play a major role in apoptosis. Antiapoptotic factors (e.g., Bcl-2) reside in the outer mitochondrial wall, and proapoptotic factors (e.g., Bax) reside in the cytosol but translocate to the mitochrondria under certain conditions. This results in the release of cytochrome c and in the activation of a key initiator caspase. Stimuli of the mitochondrial apoptotic pathways include the direct or indirect effects of reactive oxygen species, altered cellular and mitochondrial calcium homeostasis, stress signaling through the sphingomyelin/ceramide pathways (8), and so on. It is, thus, interesting that reduced vastus lateralis muscle glutathione (an important antioxidant) levels were reported in patients with COPD compared with control subjects (9), suggesting enhanced susceptibility to oxidant-induced stress. Furthermore, reduced muscle redox capacity was observed in patients with COPD after exercise training (10). Reactive oxygen species (e.g., H2O2) can increase the expression and mitochondrial translocation of proapoptotic factors (e.g., Bax and Bad). Finally, reduced serum insulin-like growth factor-1 levels, as reported in states of undernutrition, could reduce the antiapoptotic actions of the growth factor on the mitochondrial pathways (11). Although the data on muscle apoptosis provided by Agustí and coworkers (2) are new and provocative, it would be important for others to replicate and expand on these results for several reasons: (1) the percentages of apoptotic nuclei reported were extraordinarily high, and laminin or other staining techniques were not used to differentiate myonuclei from other cells (e.g., interstitial cells and endothelial cells) also subject to apoptosis; (2) the 20–30% apoptotic nuclei value in heart failure studies cited in their discussion section refers mainly to myocardial cells and not to skeletal myocytes; (3) Western blot analysis for poly(adenosine 5' diphosphate-ribose) polymerase fragments does not distinguish nuclei from different cell types; (4) transferase-mediated dUTP biotin nick end labeling assays can lack specificity and may be positive with DNA repair; (5) the evaluation of satellite cell apoptosis would be of interest for gaining an insight into impaired muscle regenerating capacity; (6) the low number of subjects studied and lack of body composition measures other than BMI; and (7) the use of young control subjects because increased apoptosis in skeletal muscle has been reported with aging (12). Apoptosis of myonuclei as an important contributing factor for sarcopenia in COPD is an attractive concept. This concept should stimulate future research efforts to validate the model, evaluate drivers and mechanisms of apoptosis in patients with COPD, and ultimately test therapeutic measures geared to impact the apoptotic cell signaling pathways in a muscle-specific fashion. FOOTNOTES This editorial has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org REFERENCES
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, interleukin-6, and their soluble receptors were significantly higher in patients with COPD with either low BMI (< 20 kg/m2) or low creatinine height index (CHI; < 80% predicted), compared with patients who had a normal BMI and CHI (
