Abstract
Exacerbations in Chronic obstructive pulmonary disease (COPD) are often accompanied by pulmonary and systemic inflammation, and are associated with an increased susceptibility to weight loss and muscle wasting. As the emphysematous phenotype in COPD appears prone to skeletal muscle wasting, the aims of this study were to evaluate in emphysematous compared to control mice following repetitive exacerbations (1) changes in muscle mass and strength and, (2) whether muscle mass recovery and its underlying processes are impaired. Emphysema was induced by intra-tracheal (IT) elastase instillations, followed by three weekly IT-LPS instillations to mimic repetitive exacerbations. Loss of muscle mass and strength were measured, and related to analyses of muscle protein turnover and myogenesis signaling in tissue collected during and following recovery. Emphysematous mice showed impaired muscle mass recovery in response to pulmonary inflammation-induced muscle atrophy. Proteolysis and protein synthesis signaling remained significantly higher in emphysematous mice during recovery from LPS. Myogenic signaling in skeletal muscle was altered, and fusion capacity of cultured muscle cells treated with plasma derived from LPS-treated emphysematous mice was significantly decreased. In conclusion, repetitive cycles of pulmonary inflammation elicit sustained muscle wasting in emphysematous mice due to impaired muscle mass recovery, which is accompanied by aberrant myogenesis.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow obstruction, inflammation and remodeling of the airways, which may include development of emphysema[1]
As we postulate that skeletal muscle atrophy in COPD is the consequence of active loss of muscle mass during disease exacerbations and impaired muscle re-growth during stable disease, we tested the hypothesis that repetitive pulmonary inflammation in emphysematous mice evokes sustained muscle atrophy resulting from impaired muscle mass recovery
Expression levels of several effectors of ubiquitin 26S-proteasome (UPS)-mediated and autophagy lysosomal pathway (ALP)-mediated proteolysis (Supplementary Fig. S2), protein synthesis (Supplementary Fig. S3), as well as regulatory kinases and transcriptional factors of these processes (Supplementary Fig. S4) were measured in gastrocnemius muscle. These analyses showed that the impaired recovery of muscle mass and strength of emphysematous mice after repetitive pulmonary inflammation cannot be attributed to sustained differences in regulation of proteolysis or protein synthesis signaling
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow obstruction, inflammation and remodeling of the airways, which may include development of emphysema[1]. Impaired muscle regeneration has been documented in these mice, suggesting that emphysema or chronic inflammation may impair the recovery of atrophied muscle[15] This suggests that muscle atrophy in COPD may follow a stepwise pattern in which each exacerbation causes an acute decrease in muscle mass, followed by impaired muscle regeneration in the stable clinical condition due to interference with protein synthesis and myogenesis due to the underlying disease. As we postulate that skeletal muscle atrophy in COPD is the consequence of active loss of muscle mass during disease exacerbations and impaired muscle re-growth during stable disease, we tested the hypothesis that repetitive pulmonary inflammation in emphysematous mice evokes sustained muscle atrophy resulting from impaired muscle mass recovery. To evaluate the potential contribution of altered protein turnover regulation and myogenesis in emphysematous mice, markers of these processes were measured during the muscle mass recovery phase following pulmonary inflammation as the second objective of this study
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