© 2008 American Thoracic Society
Muscle Atrophy and Hypertrophy Signaling Pathways in COPD: A Role in Muscle Remodeling?To the Editor:Dr. Doucet and colleagues in their article characterized muscle atrophy and growth signal transduction pathways in muscle biopsies from patients with chronic obstructive pulmonary disease (COPD) (1). Increased expression of the atrogenes MuRF1 and atrogin-1 and increased AKT phosphorylation were interpreted as increased muscle atrophy signaling and a failed attempt to increase muscle growth signaling in COPD. We dispute this conclusion and propose an alternative explanation. One major paradoxical finding concerns increased atrogin-1/MuRF1 expression in patients, which was not different between the normal and low muscle mass groups, suggesting that increased atrogene expression is not sufficient for increased protein degradation leading to atrophy. Since myofibrillar protein degradation depends on ubiquitin conjugation, which requires prior myofilament disassembly by caspases and calpains, ubiquitin conjugation of myofibrillar proteins should have been measured and related to activity of these enzymes. Based on increased atrogene expression, increased FoxO and decreased AKT activity would be expected, since FoxO is inhibited by nuclear exclusion following phosphorylation by AKT (2, 3). Surprisingly, AKT and FoxO activity were both increased in COPD muscle biopsies, and therefore AKT-independent regulation of FoxO was proposed. The assessment of FoxO activity, however, deserves attention. FoxO activity is determined by the ratio between nuclear and cytoplasmic FoxO protein levels, but only nuclear FoxO was measured. Moreover, if FoxO activity is assessed in relation to AKT, FoxO phosphorylation (P) should have been measured (4). To relate elevated P-AKT/total AKT levels to muscle growth regulation, increased phosphorylation of downstream mediators (i.e., 4E-BP1, p70S6K, and GSK-3β) was demonstrated in patients with low muscle mass. Interpretation of these data is also limited, since for each of these mediators only the ratio of phosphorylated over total protein (which was lacking) is informative on whether these pathways are activated. In the search for consistency between the apparent activation of both growth and atrophy signaling, P-4E-BP1 appeared increased in both COPD subgroups, in contrast to P-p70S6K and P-GSK-3β. Phosphorylation of 4E-BP1 allows activation of eukaryotic initiation factor 4 (eIF4), which is a major regulatory step in mRNA translational control. Based on these observations and consistent findings showing decreased type I fibers in vastus lateralis muscle of patients with severe COPD (5), we propose that the data by Doucet and coworkers may reflect COPD-associated muscle remodeling rather than muscle atrophy. In this scenario, increased atrogin-1 and MuRF1 expression is involved in specific degradation of slow-twitch proteins, while increased P-AKT and P-4E-BP1 facilitate increased translation of transcripts encoding fast-twitch proteins to establish the fiber type shift.
Maastricht University FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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