SR stress in locomotor muscles of patients with chronic obstructive pulmonary disease

Background The potential contribution of chronic dysregulation of sarcoplasmic reticulum (SR) protein homeostasis (a condition called SR stress) to skeletal muscle loss is poorly understood. We investigated the degree of activation of SR stress in locomotor muscles of patients with chronic obstructive pulmonary disease (COPD), a respiratory disease with systemic manifestations. Methods We analyzed the markers of SR stress and associated pathologies in vastus lateralis muscles of 60-65 years old male healthy controls and patients with mild (COPD stages 1 & 2) and advanced (COPD stages 3 & 4) COPD (N = 6-8 / group). Results Skeletal muscle proteins expressions of GRP94, BiP, CHOP and ATF were significantly elevated in advanced COPD (≈53%, ≈3.6 fold, ≈3.5 fold and ≈3.2 fold, respectively) compared with healthy controls. The expression of downstream markers of SR stress including apoptosis, inflammation and autophagy was increased, while the maximal activity of SR Ca2+ ATPase (SERCA) enzyme was significantly reduced in advanced COPD (≈41%) than healthy controls. Single muscle fiber diameter and cytoplasmic domain per myonucleus were significantly smaller (≈14% and 13%, respectively) in patients with advanced COPD than healthy controls. These changes in SR dysfunction were accompanied by substantially elevated levels of global oxidative stress including lipid peroxidation and mitochondrial ROS production. Conclusion Taken together, our data suggests that the muscle weakness in advanced COPD is in part driven by elevated SR stress and its pathological consequences. The data provided can lead to potential therapeutic interventions of SR dysfunction for muscle detriment in COPD.