Skeletal muscle atrophy in individuals with advanced COPD is associated with diminished quality of life, increased health resource utilization 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 signalling networks known to mediate muscle atrophy and regulate muscle regenerative capacity in rodent models, in individuals with COPD (FEV1 < 50% predicted). Nine COPD patients and nine control individuals were studied. Quadriceps femoris muscle isometric contractile force and cross-sectional area were confirmed to be significantly smaller in the COPD patients compared to controls. 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, NFBp65/p50), AKT network (AKT, GSK3, p70S6kinase), 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 COPD patients. MuRF1, Myf5, myogenin and MyoD were not differentially expressed. There were no differences in the level of phosphorylation of AKT, GSK3, p70S6kinase or IB, activation of NFBp65 or NFBp50, or level of expression of Beclin-1 or LC3, suggesting that AKT signalling was not downregulated and the NFB inflammatory pathway and autophagy were not activated in the COPD muscle. We conclude muscle atrophy associated with COPD results from the recruitment of specific regulators of ubiquitin-mediated proteolytic pathways and inhibition of muscle growth.