Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.

Summary

This study links sepsis-induced muscle atrophy to S100A8/A9-driven mitochondrial dysfunction via RAGE-mediated Drp1 phosphorylation and mitochondrial fragmentation. Inhibiting S100A8/A9, ablating RAGE, or blocking Drp1 mitigated mitochondrial damage and muscle atrophy in mice, while clinical data associated ΔSMI with 60-day mortality.

Key Findings

• ΔSMI was an independent risk factor for 60-day mortality in septic patients.
• Sepsis in mice induced skeletal muscle atrophy linked to upregulated S100a8/a9 and mitochondrial dysfunction.
• Blocking S100a8/a9 improved mitochondrial function and reduced muscle atrophy; recombinant S100a8/a9 worsened both.
• Mechanistically, S100a8/a9 engaged RAGE to phosphorylate Drp1, driving mitochondrial fragmentation; RAGE ablation or Drp1 inhibition rescued mitochondrial morphology and function.

Clinical Implications

S100A8/A9 and components of the RAGE–Drp1 axis may serve as biomarkers and therapeutic targets to prevent or treat sepsis-associated muscle wasting and weakness, pending human interventional studies.

Limitations

• Clinical component is retrospective with unspecified sample size and potential confounding.
• Translational gap remains: no human interventional data targeting the S100A8/A9–RAGE–Drp1 axis.

Future Directions

Prospective human studies to validate S100A8/A9 as a biomarker, and early-phase trials of RAGE or S100A8/A9/Drp1 modulators to prevent ICU-acquired weakness in sepsis.