Sepsis Induces Long-Term Muscle and Mitochondrial Dysfunction due to Autophagy Disruption Amenable by Urolithin A

Area of Science:

• Mitochondrial biology
• Cellular metabolism
• Muscle physiology

Background:

• Sepsis survivors frequently experience persistent muscle weakness and physical disability.
• Current pharmacological treatments for sepsis-induced muscle dysfunction are lacking.
• The underlying cellular and molecular mechanisms of this long-term weakness remain poorly understood.

Purpose of the Study:

• To investigate the molecular mechanisms of sustained muscle weakness in sepsis survivors.
• To explore the role of mitochondrial dysfunction and impaired autophagy in sepsis-induced muscle pathology.
• To evaluate the therapeutic potential of urolithin A (UA) in mitigating these impairments.

Main Methods:

• Bioinformatic analysis of vastus lateralis transcriptome in human sepsis survivors and controls.
• Weighted gene co-expression network analysis (WGCNA) and Gene Ontology (GO) enrichment analysis.
• Murine model of resuscitated sepsis to investigate mitochondrial function, autophagy flux, muscle phenotype, and response to UA treatment.

Main Results:

• Mitochondrial pathways and metabolism-related genes were persistently deregulated in sepsis survivors.
• Sepsis survivors exhibited impaired mitochondrial respiration, increased mitochondrial damage, and accumulation of autophagic vacuoles (AVs).
• Urolithin A (UA) treatment restored autophagy flux, improved mitochondrial respiration, and enhanced muscle function and mass in a murine sepsis model.

Conclusions:

• Mitochondrial dysfunction and disrupted autophagy flux are key contributors to long-term muscle impairment after sepsis.
• Sepsis induces a blockade in autophagy flux, which can be overcome by UA.
• UA demonstrates therapeutic potential for preventing and treating sepsis-induced mitochondrial and muscle deficits.