Cellular Markers of Muscle Atrophy in Chronic Obstructive Pulmonary Disease

Abstract

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 (FEV(1) < 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 (IkappaBalpha, NF-kappaBp65/p50), AKT network (AKT, GSK3beta, 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, GSK3beta, p70S6kinase, or IkappaBalpha, activation of NF-kappaBp65 or NF-kappaBp50, or level of expression of beclin-1 or LC3, suggesting that AKT signaling was not down-regulated and the NF-kappaB 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.

High CO2 Levels Cause Skeletal Muscle Atrophy via AMP-activated Kinase (AMPK), FoxO3a Protein, and Muscle-specific Ring Finger Protein 1 (MuRF1)

“…The UPS has been described to regulate skeletal muscle atrophy in patients with chronic lung diseases (43)(44)(45)(46). In addition, there have been reports of skeletal muscle atrophy via the UPS during acute lung injury and in patients with pulmonary vascular disease (47)(48)(49).…”

Cachexia in chronic obstructive pulmonary disease: new insights and therapeutic perspective

“…Even though IGF1 mRNA expression is increased in limb muscles of COPD patients, AKT activation remains unaltered 39, 45, 57. AKT activity is relatively increased in cachectic patients compared with non‐cachectic patients and healthy controls,40, 44 while the decrease in IGF1 mRNA expression in this group would generally implicate a decrease of IGF1/AKT signalling.…”

“…Furthermore, cachectic COPD patients show increased limb muscle mRNA expression of MURF1 compared with a control population 44. ATROGIN1 mRNA and protein expression are increased in limb muscles,38, 39, 40, 44, 56, 57 but unaltered in respiratory muscles of patients with COPD 55. Similarly, ATROGIN1 mRNA expression is increased in the limb muscles of smokers 58.…”

“…found that COPD patients display a higher ATROGIN1 protein expression in limb muscles than in respiratory muscles, while this difference was not found in controls 46. Additionally, limb muscle NEDD4 protein expression is increased in patients with COPD 57. Total poly‐ubiquitinated protein is increased in limb muscles of COPD patients compared with healthy controls39, 56 and in cachectic COPD patients compared with non‐cachectic COPD patients 38…”

“…Myogenic differentiation 1 (MYOD1) mRNA expression40 and protein expression appear similar in the limb muscles of COPD patients and healthy controls 57. Furthermore, Myogenin (MYOG) mRNA expression is unaltered in COPD patients 57.…”