Autophagy in locomotor muscles of patients with chronic obstructive pulmonary disease.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
1 Department of Critical Care and.
Yeting
Y
Guo
Harry R
HR
Gosker
Annemie M W J
AM
Schols
Sophia
S
Kapchinsky
Jean
J
Bourbeau
Marco
M
Sandri
R Thomas
RT
Jagoe
Richard
R
Debigaré
François
F
Maltais
Tanja
T
Taivassalo
Sabah N A
SN
Hussain
D000368:Aged; D001343:Autophagy / Q000502:physiology*; D001706:Biopsy; D005260:Female; D006801:Humans; D008124:Locomotion / Q000502:physiology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000150:complications / Q000175:diagnosis / Q000209:etiology*; D018384:Oxidative Stress / Q000502:physiology; D059748:Proteolysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D052097:Quadriceps Muscle / Q000473:pathology / Q000503:physiopathology