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Rationale: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Our previous studies have identified that nocturnal hypoxemia causes skeletal muscle loss (i.e., sarcopenia) in in vitro models of COPD. Objectives: We aimed to extend our preclinical mechanistic findings by analyzing a large sleep registry to determine whether nocturnal hypoxemia is associated with sarcopenia in patients with COPD. Methods: Sleep studies from patients with COPD (n = 479) and control subjects without COPD (n = 275) were analyzed. Patients with obstructive sleep apnea, as defined by apnea–hypopnea index ⩾ 5, were excluded. Pectoralis muscle cross-sectional area (PMcsa) was quantified using computed tomography scans performed within 1 year of the sleep study. We defined sarcopenia as less than the lowest 20% residuals for PMcsa of control subjects, which was adjusted for age and body mass index (BMI) and stratified by sex. Youden's optimal cut-point criteria were used to predict sarcopenia based on mean oxygen saturation during sleep. Additional measures of nocturnal hypoxemia were analyzed. The pectoralis muscle index (PMI) was defined as PMcsa normalized to BMI. Results: On average, males with COPD had a 16.6% lower PMI than control males (1.41 ± 0.44 vs. 1.69 ± 0.56 cm2/BMI; P < 0.001), whereas females with COPD had a 9.4% lower PMI than control females (0.96 ± 0.27 vs. 1.06 ± 0.33 cm2/BMI; P < 0.001). Males with COPD with nocturnal hypoxemia had a 9.5% decrease in PMI versus COPD with normal O2 (1.33 ± 0.39 vs. 1.47 ± 0.46 cm2/BMI; P < 0.05) and a 23.6% decrease compared with control subjects (1.33 ± 0.39 vs. 1.74 ± 0.56 cm2/BMI; P < 0.001). Females with COPD with nocturnal hypoxemia had an 11.2% decrease versus COPD with normal O2 (0.87 ± 0.26 vs. 0.98 ± 0.28 cm2/BMI; P < 0.05) and a 17.9% decrease compared with control subjects (0.87 ± 0.26 vs. 1.06 ± 0.33 cm2/BMI; P < 0.001). These findings were largely replicated using multiple measures of nocturnal hypoxemia. Conclusions: We defined sarcopenia in the pectoralis muscle using residuals that take into account age, BMI, and sex. We found that patients with COPD have a lower PMI than patients without COPD and that nocturnal hypoxemia was associated with an additional decrease in the PMI of patients with COPD. Additional prospective analyses are needed to determine a protective threshold of oxygen saturation to prevent or reverse sarcopenia due to nocturnal hypoxemia in COPD. [ABSTRACT FROM AUTHOR]

Transceptors, solute transporters that facilitate intracellular entry of molecules and also initiate intracellular signaling events, have been primarily studied in lower-order species. Ammonia, a cytotoxic endogenous metabolite, is converted to urea in hepatocytes for urinary excretion in mammals. During hyperammonemia, when hepatic metabolism is impaired, nonureagenic ammonia disposal occurs primarily in skeletal muscle. Increased ammonia uptake in skeletal muscle is mediated by a membrane-bound, 12 transmembrane domain solute transporter, Rhesus blood group-associated B glycoprotein (RhBG). We show that in addition to its transport function, RhBG interacts with myeloid differentiation primary response-88 (MyD88) to initiate an intracellular signaling cascade that culminates in activation of NFκB. We also show that ammonia-induced MyD88 signaling is independent of the canonical toll-like receptor-initiated mechanism of MyD88-dependent NFκB activation. In silico, in vitro, and in situ experiments show that the conserved cytosolic J-domain of the RhBG protein interacts with the Toll-interleukin-1 receptor (TIR) domain of MyD88. In skeletal muscle from human patients, human-induced pluripotent stem cell-derived myotubes, and myobundles show an interaction of RhBG-MyD88 during hyperammonemia. Using complementary experimental and multiomics analyses in murine myotubes and mice with muscle-specific RhBG or MyD88 deletion, we show that the RhBG-MyD88 interaction is essential for the activation of NFkB but not ammonia transport. Our studies show a paradigm of substrate-dependent regulation of transceptor function with the potential for modulation of cellular responses in mammalian systems by decoupling transport and signaling functions of transceptors. [ABSTRACT FROM AUTHOR]

Sarcopenia, defined as the loss of muscle mass and strength, is a major cause of morbidity and mortality in COPD (chronic obstructive pulmonary disease) patients. However, the molecular mechanisms that cause sarcopenia remain to be determined. In this review, we will highlight the unique molecular and metabolic perturbations that occur in the skeletal muscle of COPD patients in response to hypoxia, and emphasize important areas of future research. In particular, the mechanisms related to the glycolytic shift that occurs in skeletal muscle in response to hypoxia may occur via a hypoxia-inducible factor 1-alpha (HIF-1α)-mediated mechanism. Upregulated glycolysis in skeletal muscle promotes a unique post-translational glycosylation of proteins known as O-GlcNAcylation, which further shifts metabolism toward glycolysis. Molecular changes in the skeletal muscle of COPD patients are associated with fiber-type shifting from Type I (oxidative) muscle fibers to Type II (glycolytic) muscle fibers. The metabolic shift toward glycolysis caused by HIF-1α and O-GlcNAc modified proteins suggests a potential cause for sarcopenia in COPD, which is an emerging area of future research. [ABSTRACT FROM AUTHOR]

Background and objective: COPD is the third most common cause of death worldwide and fourth most common in the United States. In hospitalized patients with COPD, mortality, morbidity and healthcare resource utilization are high. Skeletal muscle loss is frequent in patients with COPD. However, the impact of muscle loss on adverse outcomes has not been systematically evaluated. We tested the hypothesis that patients hospitalized for COPD exacerbation with, compared to those without, a secondary diagnosis of muscle loss phenotype (all ICD‐9 codes associated with muscle loss including cachexia) will have higher mortality and cost of care. Methods: The NIS database of hospitalized patients in 2011 (1 January–31 December) in the United States was used. The impact of a muscle loss phenotype on in‐hospital mortality, LOS and cost of care for each of the 174 808 hospitalizations for COPD exacerbations was analysed. Results: Of the subjects admitted for a COPD exacerbation, 12 977 (7.4%) had a secondary diagnosis of muscle loss phenotype. A diagnosis of muscle loss phenotype was associated with significantly higher in‐hospital mortality (14.6% vs 5.7%, P < 0.001), LOS (13.3 + 17.1 vs 5.7 + 7.6, P < 0.001) and median hospital charge per patient ($13 947 vs $6610, P < 0.001). Multivariate regression analysis showed that muscle loss phenotype increased mortality by 111% (95% CI: 2.0–2.2, P < 0.001), LOS by 68.4% (P < 0.001) and the direct cost of care by 83.7% (P < 0.001) compared to those without muscle loss. Conclusion: In‐hospital mortality, LOS and healthcare costs are higher in patients with COPD exacerbations and a muscle loss phenotype. Using a large national data set of patients admitted for a COPD exacerbation with and without muscle loss phenotype, we showed that mortality, LOS and cost are considerably higher in patients with muscle loss phenotype. We demonstrated the need for targeted interventions to improve outcomes for patients with COPD. See relatedEditorial [ABSTRACT FROM AUTHOR]