Autophagy in Locomotor Muscles of Patients with Chronic Obstructive Pulmonary Disease

• Published in: American journal of respiratory and critical care medicine Vol. 188; no. 11; pp. 1313 - 1320
• Main Authors: Guo, Yeting, Gosker, Harry R., Schols, Annemie M. W. J., Kapchinsky, Sophia, Bourbeau, Jean, Sandri, Marco, Jagoe, R. Thomas, Debigaré, Richard, Maltais, François, Taivassalo, Tanja, Hussain, Sabah N. A.
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 01.12.2013
• Subjects: Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Atrophy; Autophagy; Autophagy - physiology; Biological and medical sciences; Biopsy; Body mass index; Chronic obstructive pulmonary disease; Chronic obstructive pulmonary disease, asthma; Female; Gene expression; Humans; Intensive care medicine; Kinases; Locomotion - physiology; Male; Medical sciences; Metabolism; Microscopy; Middle Aged; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular Atrophy - complications; Muscular Atrophy - diagnosis; Muscular Atrophy - etiology; Oxidative stress; Oxidative Stress - physiology; Pneumology; Proteins; Proteolysis; Pulmonary Disease, Chronic Obstructive - complications; Pulmonary Disease, Chronic Obstructive - pathology; Pulmonary Disease, Chronic Obstructive - physiopathology; Quadriceps Muscle - pathology; Quadriceps Muscle - physiopathology; Transcription factors; Human; Lung disease; Multicatalytic endopeptidase complex; proteasome; Intensive care; autophagy; protein kinase B (AKT); Enzyme; Respiratory disease; Akt protein kinase; Patient; Atrophy; Peptidases; Chronic; Proteolysis; Hydrolases; Bronchus disease; Chronic obstructive pulmonary disease; Muscle; Obstructive pulmonary disease; Resuscitation; COPD
• DOI: 10.1164/rccm.201304-0732OC
• ISSN: 1073-449X; 1535-4970

Locomotor muscle atrophy develops in patients with chronic obstructive pulmonary disease (COPD) partly because of increased protein degradation by the ubiquitin-proteasome system. It is not known if autophagy also contributes to protein degradation. To investigate whether autophagy is enhanced in locomotor muscles of stable patients with COPD, to quantify autophagy-related gene expression in these muscles, and to identify mechanisms of autophagy induction. Muscle biopsies were obtained from two cohorts of control subjects and patients with COPD and the numbers of autophagosomes in the vastus lateralis and tibialis anterior muscles, the levels of LC3B protein lipidation, and the expression of autophagy-related genes were measured in the vastus lateralis muscle. To investigate potential pathways that might induce the activation of autophagy, measures were taken of protein kinase B (AKT), mTORC1, and AMPK pathway activation, transcription factor regulation, proteasome activation, and oxidative stress. Autophagy is enhanced in the locomotor muscles of patients with COPD as shown by significantly higher numbers of autophagosomes in affected muscles as compared with control subjects. Autophagosome number inversely correlates with FEV1. In the vastus lateralis, LC3B protein lipidation is increased by COPD and the expression of autophagy-related gene expressions is up-regulated. LC3B lipidation inversely correlates with thigh cross-sectional area, FEV1, and FEV1/FVC ratio. Enhanced autophagy is associated with activation of the AMPK pathway and FOXO transcription factors, inhibition of the mTORC1 and AKT pathways, and the development of oxidative stress. Autophagy is significantly enhanced in locomotor muscles of stable patients with COPD. The degree of autophagy correlates with severity of muscle atrophy and lung function impairment.