Muscle Atrophy And Hypertrophy Signaling In Patients With Chronic Obstructive Pulmonary Disease

Muscle Atrophy and Hypertrophy Signaling in Patients with Chronic Obstructive Pulmonary Disease
` ´ ´ ´ Marieve Doucet1, Aaron P. Russell2,3, Bertrand Leger2, Richard Debigare1, Denis R. Joanisse4, Marc-Andre Caron1, Pierre LeBlanc1, and Francois Maltais1 ¸
ˆ ´ ´ Centre de Recherche de l’Hopital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l’Universite Laval, Laval, Quebec,Canada; ´ Clinique Romande de Readaptation SUVA Care, Sion, Switzerland; 3Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Australia; and 4Division de Kinesiologie, Universite Laval, Laval, Quebec, Canada ´ ´ ´
2 1

Rationale: The molecular mechanisms of muscle atrophy in chronic obstructive pulmonary disease (COPD) are poorlyunderstood. In wasted animals, muscle mass is regulated by several AKT-related signaling pathways. Objectives: To measure the protein expression of AKT, forkhead box class O (FoxO)-1 and -3, atrogin-1, the phosphophrylated form of AKT, p70S6K glycogen synthase kinase-3 (GSK-3 ), eukaryotic translation initiation factor 4E binding protein-1 (4E-BP1), and the mRNA expression of atrogin-1, musclering 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. Methods: Protein contents and mRNA expression were measured by Western blot and quantitative polymerase chain reaction,respectively. Measurements and Main Results: 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, p70S6K, GSK-3 , and FoxO-3 protein levels were similar. Patients with COPD with muscle atrophy showed an increased expression of p70S6K, GSK-3, and 4EBP1 compared with patients with COPD with preserved muscle mass. Conclusions: 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 withCOPD with muscle atrophy could represent an attempt to restore muscle mass. Keywords: chronic obstructive pulmonary disease; muscle wasting; AKT; forkhead box class O-1; E3-ligases

AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject

Muscle atrophy is common in patients with chronic obstructive pulmonary disease (COPD). It is associated with increased mortality. However, the mechanismsleading to muscle wasting remain to be elucidated.
What This Study Adds to the Field

An increase in atrogin-1 and MuRF1 mRNA and FoxO-1 protein content was observed in the quadriceps of patients with COPD. The overexpression of the muscle hypertrophic signaling pathways found in patients with COPD with muscle atrophy could represent an attempt to restore muscle mass.

Skeletal muscle atrophyis an important systemic consequence of chronic obstructive pulmonary disease (COPD) (1, 2). In patients with severe COPD, reduced mid-thigh muscle crosssectional area (MTCSA) has a strong impact on mortality (3). Although the biochemical pathways engaged in the development of muscle atrophy are poorly understood, an imbalance between

(Received in original form May 26, 2006; accepted in finalform May 2, 2007 ) ´ ´ Supported by Fonds de la Recherche en Sante du Quebec in the form of salary ˆ support (M.D.), by a grant from the Centre de Recherche de l’Hopital Laval (M.-A.C.), Fonds National pour la Recherche Scientifique grant 3200B0-15936 (B.L.), and by Canadian Institutes of Health Research grant MOP-84091, and by the Romain Pouwels Research Fund. D.R.J. and F.M. are research...