Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands.
Department of Biochemistry, Microbiology and Immunology, Ottawa Hospital Research Institute, Ottawa, Canada.
Respir Res. 2018 May 2;19(1):80. doi: 10.1186/s12931-018-0753-8.
Pulmonary inflammation in response to respiratory infections can evoke muscle wasting. Increased activity of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Since poly-Ub conjugation is required for UPS-mediated proteolysis and has been implicated in the ALP, we assessed the effect of impaired ubiquitin conjugation on muscle atrophy and recovery following pulmonary inflammation, and compared activation and suppression of these proteolytic systems to protein synthesis regulation.
Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS. Proteolysis (UPS and ALP) and synthesis signaling were examined in gastrocnemius muscle homogenates. Ub-conjugation-dependency of muscle atrophy and recovery was addressed using Ub-K48R (K48R) mice with attenuated poly-ubiquitin conjugation, and compared to UBWT control mice.
Pulmonary inflammation caused a decrease in skeletal muscle mass which was accompanied by a rapid increase in expression of UPS and ALP constituents and reduction in protein synthesis signaling acutely after LPS. Muscle atrophy was attenuated in K48R mice, while ALP and protein synthesis signaling were not affected. Muscle mass recovery starting 72 h post LPS, correlated with reduced expression of UPS and ALP constituents and restoration of protein synthesis signaling. K48R mice however displayed impaired recovery of muscle mass.
Pulmonary inflammation-induced muscle atrophy is in part attributable to UPS-mediated proteolysis, as activation of ALP- and suppression of protein synthesis signaling occur independently of poly-Ub conjugation during muscle atrophy. Recovery of muscle mass following pulmonary inflammation involves inverse regulation of proteolysis and protein synthesis signaling, and requires a functional poly-Ub conjugation.
呼吸道感染引起的肺部炎症会引发肌肉消耗。泛素（Ub）-蛋白酶体系统（UPS）和自噬溶酶体途径（ALP）的活性增加与炎症诱导的肌肉萎缩有关。由于多 Ub 连接对于 UPS 介导的蛋白水解是必需的，并且与 ALP 有关，因此我们评估了泛素连接受损对肺部炎症后肌肉萎缩和恢复的影响，并比较了这些蛋白水解系统的激活和抑制与蛋白质合成调节。
通过气管内滴注 LPS 诱导小鼠肺部炎症。在比目鱼肌匀浆中检测蛋白水解（UPS 和 ALP）和合成信号。使用 Ub-K48R（K48R）小鼠，其多泛素连接减弱，研究 Ub 连接依赖性的肌肉萎缩和恢复，并与 UBWT 对照小鼠进行比较。
肺部炎症导致骨骼肌质量减少，这伴随着 UPS 和 ALP 成分的迅速增加和 LPS 后急性蛋白质合成信号的减少。K48R 小鼠的肌肉萎缩减轻，而 ALP 和蛋白质合成信号不受影响。从 LPS 后 72 小时开始，肌肉质量恢复与 UPS 和 ALP 成分的表达减少以及蛋白质合成信号的恢复相关。然而，K48R 小鼠的肌肉质量恢复受损。
肺部炎症引起的肌肉萎缩部分归因于 UPS 介导的蛋白水解，因为在肌肉萎缩期间，ALP 的激活和蛋白质合成信号的抑制独立于多 Ub 连接。肺部炎症后肌肉质量的恢复涉及蛋白水解和蛋白质合成信号的反向调节，并且需要功能性多 Ub 连接。
