title: Impaired exercise training-induced muscle fiber hypertrophy and Akt/mTOR pathway activation in hypoxemic patients with COPD.
abstract: Exercise training (ExTr) is largely used to improve functional capacity in patients with chronic obstructive pulmonary disease (COPD). However, ExTr only partially restores muscle function in patients with COPD, suggesting that confounding factors may limit the efficiency of ExTr. In the present study, we hypothesized that skeletal muscle adaptations triggered by ExTr could be compromised in hypoxemic patients with COPD. Vastus lateralis muscle biopsies were obtained from patients with COPD who were either normoxemic (n = 15, resting arterial Po2 = 68.5 ± 1.5 mmHg) or hypoxemic (n = 8, resting arterial Po2 = 57.0 ± 1.0 mmHg) before and after a 2-mo ExTr program. ExTr induced a significant increase in exercise capacity both in normoxemic and hypoxemic patients with COPD. However, ExTr increased citrate synthase and lactate dehydrogenase enzyme activities only in skeletal muscle of normoxemic patients. Similarly, muscle fiber cross-sectional area and capillary-to-fiber ratio were increased only in patients who were normoxemic. Expression of atrogenes (MuRF1, MAFbx/Atrogin-1) and autophagy-related genes (Beclin, LC3, Bnip, Gabarapl) remained unchanged in both groups. Phosphorylation of Akt (Ser473), GSK-3β (Ser9), and p70S6k (Thr389) was nonsignificantly increased in normoxemic patients in response to ExTr, but it was significantly decreased in hypoxemic patients. We further showed on C2C12 myotubes that hypoxia completely prevented insulin-like growth factor-1-induced phosphorylation of Akt, GSK-3β, and p70S6K. Together, our observations suggest a role for hypoxemia in the adaptive response of skeletal muscle of patients with COPD in an ExTr program.
authors.affiliation: Service de Physiologie Clinique et de l'Exercice, Pôle NOL, CHU Saint Étienne, France; Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Étienne, France; and frederic.costes@chu-st-etienne.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Costes
authors.affiliation: NUTRIM School for Nutrition, Toxicology and Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Gosker
authors.affiliation: Service de Physiologie Clinique et de l'Exercice, Pôle NOL, CHU Saint Étienne, France; Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Étienne, France; and.
authors.forename: Léonard
authors.initials: L
authors.lastname: Feasson
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Étienne, France; and.
authors.forename: Marine
authors.initials: M
authors.lastname: Desgeorges
authors.affiliation: NUTRIM School for Nutrition, Toxicology and Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Kelders
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Étienne, France; and.
authors.forename: Josiane
authors.initials: J
authors.lastname: Castells
authors.affiliation: NUTRIM School for Nutrition, Toxicology and Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Annemie
authors.initials: A
authors.lastname: Schols
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Étienne, France; and.
authors.forename: Damien
authors.initials: D
authors.lastname: Freyssenet
mesh_terms: D000818:Animals; D002460:Cell Line; D002950:Citrate (si)-Synthase / Q000378:metabolism; D005260:Female; D006801:Humans; D006984:Hypertrophy; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D064797:Physical Conditioning, Human / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D007334:Insulin-Like Growth Factor I; D007770:L-Lactate Dehydrogenase; D002950:Citrate (si)-Synthase; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: COPD; exercise training; hypoxia; skeletal muscle