Deletion of Nlrp3 protects from inflammation-induced skeletal muscle atrophy
Nora Huang1,2, Melanie Kny1, Fabian Riediger1,3
1Experimental and Clinical Research Center (ECRC), Charité-Universitätsmedizin Berlin, Max Delbrück Center (MDC) for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Background:
Critically ill patients develop atrophic muscle failure, which increases morbidity and mortality. Interleukin-1β (IL-1β) is activated early in sepsis. Whether IL-1β acts directly on muscle cells and whether its inhibition prevents atrophy is unknown. We aimed to investigate if IL-1β activation via the Nlrp3 inflammasome is involved in inflammation-induced atrophy.
Methods:
We performed an experimental study and prospective animal trial. The effect of IL-1β on differentiated C2C12 muscle cells was investigated by analyzing gene-and-protein expression, and atrophy response. Polymicrobial sepsis was induced by cecum ligation and puncture surgery in Nlrp3 knockout and wild type mice. Skeletal muscle morphology, gene and protein expression, and atrophy markers were used to analyze the atrophy response. Immunostaining and reporter-gene assays showed that IL-1β signaling is contained and active in myocytes.
Results:
Immunostaining and reporter gene assays showed that IL-1β signaling is contained and active in myocytes. IL-1β increased Il6 and atrogene gene expression resulting in myocyte atrophy. Nlrp3 knockout mice showed reduced IL-1β serum levels in sepsis. As determined by muscle morphology, organ weights, gene expression, and protein content, muscle atrophy was attenuated in septic Nlrp3 knockout mice, compared to septic wild-type mice 96 h after surgery.
Conclusions:
IL-1β directly acts on myocytes to cause atrophy in sepsis. Inhibition of IL-1β activation by targeting Nlrp3 could be useful to prevent inflammation-induced muscle failure in critically ill patients.
Insights
Interleukin-1β (IL-1β) directly causes muscle atrophy in sepsis by acting on myocytes. Targeting the Nlrp3 inflammasome to inhibit IL-1β activation may prevent muscle failure in critically ill patients.
Area of Science:
- Biomedical Science
- Cell Biology
- Inflammation Research
Background:
- Critically ill patients often suffer from muscle atrophy, a condition linked to increased morbidity and mortality.
- Interleukin-1β (IL-1β) is known to be activated early during sepsis.
- The direct role of IL-1β in muscle cell atrophy and the potential benefits of its inhibition remained unclear.
Purpose of the Study:
- To investigate whether IL-1β directly affects muscle cells and contributes to inflammation-induced atrophy.
- To explore the involvement of the Nlrp3 inflammasome in IL-1β activation and subsequent muscle atrophy during sepsis.
Main Methods:
- Experiments were conducted on differentiated C2C12 muscle cells to assess the impact of IL-1β on gene and protein expression and atrophy.
- A polymicrobial sepsis model was induced in Nlrp3 knockout and wild-type mice via cecum ligation and puncture.
- Muscle morphology, organ weights, gene expression, protein content, and atrophy markers were analyzed to evaluate the atrophy response.
Main Results:
- IL-1β was found to directly increase the expression of Il6 and atrogene genes, leading to myocyte atrophy.
- Septic Nlrp3 knockout mice exhibited reduced IL-1β serum levels compared to wild-type mice.
- Muscle atrophy was significantly attenuated in Nlrp3 knockout mice 96 hours post-sepsis induction, as evidenced by morphological and molecular analyses.
Conclusions:
- Interleukin-1β directly induces muscle atrophy in myocytes during sepsis.
- Inhibiting IL-1β activation by targeting the Nlrp3 inflammasome presents a potential therapeutic strategy to prevent muscle wasting in critically ill patients.
