Abstract
BackgroundPulmonary 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.MethodsPulmonary 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.ResultsPulmonary 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.ConclusionPulmonary 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.
Highlights
Pulmonary inflammation in response to respiratory infections can evoke muscle wasting
As the Ub K48R substitution does not affect autophagy lysosome pathway (ALP)- and protein synthesis signaling during muscle loss, we conclude that muscle atrophy observed following pulmonary inflammation is in part dependent on UPSmediated proteolysis
The residual muscle mass loss in K48R mice observed up to 72 h post-LPS implies a contribution of increased autophagy and reduced protein synthesis signaling to muscle atrophy following pulmonary inflammation
Summary
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. Muscle proteolysis involves multiple systems, including the ubiquitin 26Sproteasome system (UPS) and the autophagy lysosomal pathway (ALP) [9,10,11]. In skeletal muscle, these include MuRF1 and Atrogin-1, and E3-ligase expression levels appear a rate limiting step in UPS-mediated proteolysis [13, 14]. UPS dependency of autophagy termination [16], suggests that ALP mediated proteolysis may involve Ub conjugation
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