Increased autophagy and reduced protein synthesis signaling are involved in pulmonary inflammation-induced skeletal muscle atrophy

Abstract

Background: Exacerbations in COPD are often accompanied by pulmonary and systemic inflammation, and are associated with an increased susceptibility to and prevalence of weight loss and muscle wasting. Both the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Our aim was to provide a more comprehensive overview of protein turnover regulation in skeletal muscle atrophy following pulmonary inflammation, and to investigate UPS dependency of this process. Methods: Pulmonary inflammation was induced in mice by intra-tracheal instillation of LPS. Protein breakdown by UPS (MuRF1, Atrogin-1) and ALP (LC3B-II, p62), and synthesis signaling (p-4EBP1, p-S6) were examined in muscle homogenates using western blot and Q-PCR analyses. UPS-dependency of muscle atrophy was addressed using Ub-K48R mice with attenuated poly-ubiquitin conjugation. Results: Administration of intratracheal LPS caused a rapid decrease in skeletal muscle mass which was less pronounced in the Ub-K48R- compared to control mice. Expression and activity of UPS and ALP constituents increased significantly, suggesting induction of these proteolysis pathways acutely after LPS, whereas markers for protein synthesis signaling were decreased. Changes in ALP and synthesis regulation during muscle atrophy were similar in Ub-K48R and control mice. Conclusion: These data reveal that pulmonary inflammation-induced changes in ALP- and synthesis signaling are regulated independently of poly-Ub conjugation, and suggest a contribution of these processes to muscle atrophy in conjunction with UPS-mediated proteolysis.