ECSS Paris 2023: OP-PN27
INTRODUCTION: Ageing is accompanied by a persistent, low-grade systemic inflammatory state, termed “inflammaging”, together with mitochondrial dysfunction. One mechanistic candidate that has recently been proposed to bridge inflammation with mitochondrial dysfunction is the receptor for advanced glycation end-products (RAGE). While increased RAGE expression has been documented in skeletal muscle under pathological conditions, its involvement in healthy human skeletal muscle ageing remains largely unexplored, questioning the relevance of this receptor as a target in physiological ageing. METHODS: Healthy young and middle-aged sedentary women (27.5 +/- 5.8 vs. 57.4 +/- 5.8, p<0.01) underwent standardised cardiorespiratory fitness testing. Skeletal muscle biopsies from vastus lateralis and resting blood samples were collected. Mitochondrial content and respiration were assessed using enzymatic assays and high-resolution respirometry. Skeletal muscle RAGE abundance, circulating RAGE ligands (S100A12, HMGB1, mt-DNA), and inflammatory markers (IL-6, IL-1B, TNF-a and CRP) were quantified using immunoblotting, ELISA or qRT-PCR. RNA sequencing was performed to identify age-related changes in RAGE-associated signalling pathways. RESULTS: Skeletal muscle RAGE content was 2.3-fold higher in middle-aged group (p<0.01) and positively correlated with age (r=0.66, p<0.01). Plasma levels of S100A12 and mt-DNA were increased in the middle-aged group (p<0.05). Plasma TNFa levels were 2.6-fold higher in middle-aged women (p<0.05), whereas IL-6, IL-1B, and CRP levels remained unchanged between groups. Mitochondrial analysis revealed a 30% increase in complex I-driven proton leak in skeletal muscle from middle-aged women (p<0.01), whereas ADP-stimulated respiration supported either by complex I or complex I+II was not different between groups. RNA sequencing identified 25 differentially expressed RAGE-related genes. Following normalization for cell-type composition, four genes remained differentially expressed (DDOT, JAK2, RAF1, and RHOA). CONCLUSION: These findings provide novel evidence that the expression of RAGE increases in the skeletal muscle of healthy ageing women and may represent a mechanistic link integrating inflammaging and mitochondrial alterations. Skeletal muscle may therefore act not only as a target but also as a contributor to systemic inflammaging through RAGE-mediated mitochondrial dysfunction. This work offers new perspectives for understanding the molecular mechanisms underlying healthy muscle ageing.
Read CV Frédéric DaussinECSS Paris 2023: OP-PN27