© 2008 American Thoracic Society
Muscle Atrophy and Hypertrophy Signaling Pathways in COPD: A Role in Muscle Remodeling?From the Authors:We thank Drs. Langen and Schols for their interest in our article (1) and for kindly sharing their suggestions about how to interpret our data. As in any human investigation, the amount of tissue available for research was limited and choices had to be made. We focused on the active form (phosphorylated) of proteins of interest (p70S6K, 4E-BP1, GSK-3β) and on nuclear fractions for the others (FoxO-1, -3). These choices were made because these forms are directly responsible for activation/inactivation of their downstream effectors (2–4). Drs. Langen and Schols suggest that the activity of the FoxO proteins should be determined by the ratio between the FoxO nuclear and cytoplasmic levels. This ratio does not provide better evidence of FoxO activity. FoxO must be translocated to the nucleus to be transcriptionally active (4). Therefore, comparing the levels of nuclear FoxO between groups is more indicative of actual FoxO activity. Our finding that FoxO-1 up-regulation could not be explained by a reduction of phosphorylated AKT is important (2–4). AKT-independent FoxO-1 up-regulation has previously been observed in human primary breast tumors in which phosphorylated AKT is undetectable (5). Additionally, decreased levels of active AKT protein in atrophied muscle of patients with amyotrophic lateral sclerosis did not reveal the expected increase in nuclear FoxO content (6). Therefore, it appears that under certain conditions, AKT and FoxO regulation can be independent of each other. Drs. Langen and Schols propose that a fiber-type shift may explain the up-regulation of the hypertrophy signalization in patients with chronic obstructive pulmonary disease (COPD) and muscle atrophy and suggest that this finding may be more reflective of muscle remodeling than of muscle atrophy. We have data that were not provided with our article (1), which indicate that the fiber-type distribution was similar between patients with muscle atrophy and patients with preserved muscle mass (Figure 1A). Atrophy was also present in all fiber types (Figure 1B).
Last, no statistically significant correlations were found between the content of the different muscle proteins that were examined in our study and fiber-typing or cross-sectional area. These supplementary data are not consistent with the interpretation that the molecular signaling differences between the two groups of patients with COPD could be explained by a remodeling process related to a fiber-type shift. We are grateful for the opportunity to clarify some issues regarding our study. Some pieces of the puzzle of muscle atrophy in COPD have been laid out, and many more are expected to come.
Centre de Recherche de l'Hôpital Laval FOOTNOTES Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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