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Cellular Markers of Muscle Atrophy in Chronic Obstructive Pulmonary Disease

¹ Department of Medicine and ⁵ Department of Radiology and St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; ² Department of Physical Therapy, University of Toronto and Toronto Rehab Institute, Toronto, Ontario, Canada; ³ Department of Surgery, McMaster University, Hamilton, Ontario, Canada; and ⁴ Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Jane Batt, M.D., Ph.D., Room 7344, Medical Sciences Building, 1 Kings College Circle, University of Toronto, Toronto, ON, M5S 1A8 Canada. E-mail: jane.batt{at}utoronto.ca

Skeletal muscle atrophy in individuals with advanced chronic obstructive pulmonary disease (COPD) is associated with diminished quality of life, increased health resource use, and worsened survival. Muscle wasting results from an imbalance between protein degradation and synthesis, and is enhanced by decreased regenerative repair. We investigated the activation of cellular signaling networks known to mediate muscle atrophy and regulate muscle regenerative capacity in rodent models, in individuals with COPD (FEV₁ < 50% predicted). Nine patients with COPD and nine control individuals were studied. Quadriceps femoris muscle isometric contractile force and cross-sectional area were confirmed to be significantly smaller in the patients with COPD compared with control subjects. The vastus lateralis muscle was biopsied and muscle transcript and/or protein levels of key components of ubiquitin-mediated proteolytic systems (MuRF1, atrogin-1, Nedd4), inflammatory mediators (IB, NF-Bp65/p50), AKT network (AKT, GSK3β, p70S6 kinase), mediators of autophagy (beclin-1, LC3), and myogenesis (myogenin, MyoD, Myf5, myostatin) were determined. Atrogin-1 and Nedd4, two ligases regulating ubiquitin-mediated protein degradation and myostatin, a negative regulator of muscle growth, were significantly increased in the muscle of patients with COPD. MuRF1, Myf5, myogenin, and MyoD were not differentially expressed. There were no differences in the level of phosphorylation of AKT, GSK3β, p70S6kinase, or IB, activation of NF-Bp65 or NF-Bp50, or level of expression of beclin-1 or LC3, suggesting that AKT signaling was not down-regulated and the NF-B inflammatory pathway and autophagy were not activated in the COPD muscle. We conclude that muscle atrophy associated with COPD results from the recruitment of specific regulators of ubiquitin-mediated proteolytic pathways and inhibition of muscle growth.

Key Words: vastus lateralis • ubiquitin ligase • myostatin • neural precursor cell–expressed developmentally down-regulated 4 • atrogin-1

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