Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease

• Published in: American journal of respiratory and critical care medicine Vol. 176; no. 3; pp. 261 - 269
• Main Authors: Doucet, Marieve, Russell, Aaron P, Leger, Bertrand, Debigare, Richard, Joanisse, Denis R, Caron, Marc-Andre, LeBlanc, Pierre, Maltais, Francois
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 01.08.2007; American Lung Association; American Thoracic Society
• Subjects: Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anthropometry; Atrophy; Biological and medical sciences; Chronic illnesses; Chronic obstructive pulmonary disease; Chronic obstructive pulmonary disease, asthma; Exercise; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Humans; Intensive care medicine; Kinases; Male; Medical sciences; Middle Aged; Multiple System Atrophy - etiology; Multiple System Atrophy - metabolism; Muscle Proteins - metabolism; Muscular Atrophy - physiopathology; Musculoskeletal system; Phosphorylation; Pneumology; Protein synthesis; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary Disease, Chronic Obstructive - complications; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Signal Transduction - physiology; SKP Cullin F-Box Protein Ligases - metabolism; Tripartite Motif Proteins; Ubiquitin-Protein Ligases - metabolism; Human; Lung disease; Intensive care; E3-ligases; Respiratory disease; Enzyme; Chronic disease; AKT; muscle wasting; Atrophy; Ligases; Bronchus disease; forkhead box class 0-1; Obstructive pulmonary disease; Resuscitation; chronic obstructive pulmonary disease
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200605-704OC

The molecular mechanisms of muscle atrophy in chronic obstructive pulmonary disease (COPD) are poorly understood. In wasted animals, muscle mass is regulated by several AKT-related signaling pathways. To measure the protein expression of AKT, forkhead box class O (FoxO)-1 and -3, atrogin-1, the phosphophrylated form of AKT, p70(S6K) glycogen synthase kinase-3beta (GSK-3beta), eukaryotic translation initiation factor 4E binding protein-1 (4E-BP1), and the mRNA expression of atrogin-1, muscle ring finger (MuRF) protein 1, and FoxO-1 and -3 in the quadriceps of 12 patients with COPD with muscle atrophy and 10 healthy control subjects. Five patients with COPD with preserved muscle mass were subsequently recruited and were compared with six patients with low muscle mass. Protein contents and mRNA expression were measured by Western blot and quantitative polymerase chain reaction, respectively. The levels of atrogin-1 and MuRF1 mRNA, and of phosphorylated AKT and 4E-BP1 and FoxO-1 proteins, were increased in patients with COPD with muscle atrophy compared with healthy control subjects, whereas atrogin-1, p70(S6K), GSK-3beta, and FoxO-3 protein levels were similar. Patients with COPD with muscle atrophy showed an increased expression of p70(S6K), GSK-3beta, and 4E-BP1 compared with patients with COPD with preserved muscle mass. An increase in atrogin-1 and MuRF1 mRNA and FoxO-1 protein content was observed in the quadriceps of patients with COPD. The transcriptional regulation of atrogin-1 and MuRF1 may occur via FoxO-1, but independently of AKT. The overexpression of the muscle hypertrophic signaling pathways found in patients with COPD with muscle atrophy could represent an attempt to restore muscle mass.