# RAGE contributes to persistent sepsis-induced muscle and mitochondrial alterations

## TL;DR

Sepsis can cause long-term muscle weakness and mitochondrial issues in mice, which may be reduced by targeting RAGE.

## Contribution

This study is the first to show that RAGE plays a role in persistent muscle dysfunction after sepsis in mice.

## Key findings

- Sepsis leads to long-term muscle weakness and mitochondrial dysfunction in mice.
- RAGE knockout mice do not show long-term muscle issues after sepsis.
- Muscle inflammation and mitochondrial stress persist three months after sepsis.

## Abstract

A majority of patients surviving sepsis develop muscle weakness. However, the underlying cellular and molecular pathways remain largely unexplored. To determine whether sepsis leads to long-term persistent muscular consequences and to identify the underlying mechanisms, we used a murine model of reanimated sepsis induced by intraperitoneal injection of a heterologous stool slurry. Muscles were analyzed 3 months later. The oxidative muscle exhibited reduced fatigue resistance and decreased mitochondrial respiration, without a corresponding reduction in mitochondrial OXPHOS proteins. Glycolytic and mixed muscle fibres were atrophied. Markers of oxidative and mitochondrial stress, as well as genes involved in mitochondrial fission, remained present 3 months after sepsis. Low-grade, but significant, muscular inflammation was also measured. Specifically, both the NLRP3 inflammasome and the receptor of Advanced Glycation End-products (RAGE) axis were upregulated. Interestingly, long-term sepsis-induced muscular consequences were not observed in RAGE knockout mice. Overall, we describe for the first time in mice that sepsis causes long-lasting muscle dysfunction after recovery, including mitochondrial alterations and low-grade inflammation, and that RAGE may represent a promising target to mitigate long-term muscle alterations induced by sepsis.

The online version contains supplementary material available at 10.1038/s41598-025-28645-8.