RAGE contributes to persistent sepsis-induced muscle and mitochondrial alterations

Area of Science:

• Biomedical Science
• Molecular Biology
• Physiology

Background:

• Sepsis survivors frequently develop persistent muscle weakness, but the underlying mechanisms are poorly understood.
• Investigating the long-term cellular and molecular consequences of sepsis on muscle is crucial for patient recovery.

Purpose of the Study:

• To determine if sepsis causes long-term muscle dysfunction in a murine model.
• To identify the molecular mechanisms driving sepsis-induced long-term muscle alterations.
• To explore the role of the receptor of Advanced Glycation End-products (RAGE) in these processes.

Main Methods:

• A murine model of reanimated sepsis was established using intraperitoneal injection of stool slurry.
• Muscles were analyzed three months post-sepsis for functional, cellular, and molecular changes.
• Key pathways investigated included mitochondrial respiration, inflammation, oxidative stress, and the RAGE axis.

Main Results:

• Sepsis induced persistent muscle fatigue, reduced mitochondrial respiration, and muscle fiber atrophy three months later.
• Markers of oxidative stress, mitochondrial fission, and low-grade inflammation (NLRP3 inflammasome, RAGE) were upregulated.
• RAGE knockout mice did not exhibit long-term sepsis-induced muscle dysfunction, suggesting RAGE's critical role.

Conclusions:

• Sepsis leads to long-lasting muscle dysfunction, characterized by mitochondrial alterations and chronic inflammation.
• The receptor of Advanced Glycation End-products (RAGE) pathway is implicated in sepsis-induced persistent muscle weakness.
• Targeting RAGE presents a potential therapeutic strategy to prevent or treat long-term muscle complications after sepsis.