Comprehensive metabolic flux analysis to explain skeletal muscle weakness in COPD.
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BACKGROUND & AIMS: Metabolic characterization of a well-defined group of patients could be a powerful tool in revealing metabolic signatures to explain limb muscle weakness in chronic diseases. Studies are currently limited in Chronic Obstructive Pulmonary Disease (COPD) to the identification of differential amino acid concentrations but lack comprehensive analysis of the flux through relevant muscle function related metabolic pathways. METHODS: In 23 stable patients with moderate to very severe COPD and 19 healthy controls, a comprehensive metabolic flux analysis was conducted by administering an intravenous pulse and primed constant infusion of multiple stable tracers of amino acids known to play a role in muscle health. Blood samples were obtained to calculate production (WBP) and interconversion rates, and plasma concentrations of these amino acids. Lower and upper limb muscle strength, muscle mass, lung function, physical activity level, and disease history and characteristics were assessed. RESULTS: The COPD group was characterized by lower and upper limb muscle weakness (P<0.01) despite preserved muscle mass. Higher values were found in COPD for plasma glutamine, WBP of leucine (P<0.001), 3-methylhistidine (P<0.01) (marker of enhanced myofibrillar protein breakdown), citrulline (P<0.05), and arginine to citrulline conversion (P<0.05) (reflecting enhanced nitric oxide synthesis). Plasma concentration of -hydroxy -methylbutyrate (HMB with anticatabolic, anabolic and contractile properties), WBP of glycine (precursor of creatine and glutathione), and transcutaneous O2 saturation explained up to 79% and 65% of the variation in strength of the lower and upper limb muscles, respectively, in COPD. CONCLUSIONS: Comprehensive metabolic flux analysis revealed a homogenous metabolic signature in stable patients with COPD and a specific metabolic profile in those with skeletal muscle weakness. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov; No. NCT01787682; URL: www.clinicaltrials.gov.
