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Sagmeister, M. S.

Publications and source records attributed to Sagmeister, M. S..

2 recordsLinked to original sources
bioRxiv2025

Systemic drivers and molecular mechanisms of sarcopenia in aetiology-specific end-stage liver disease

IntroductionPatients with end-stage liver disease (ESLD) often present with sarcopenia, defined as loss of skeletal muscle mass and quality, which is associated with reduced quality of life and increased mortality. However, the molecular mechanisms driving sarcopenia in ESLD are not fully understood and there are currently no therapeutic interventions. This study aimed to identify potential circulating factors contributing to sarcopenia progression in ESLD by assessing their role in driving transcriptomic alterations in skeletal muscle. MethodsQuadriceps muscle tissue, plasma and serum were obtained from ESLD patients (n=24) and age/sex-matched healthy controls (HC; n=18) (clinical trial ID: NCT04734496, ethical approval 18/WM/0167). Total RNA from snap-frozen vastus lateralis muscle biopsies underwent RNA sequencing (Illumina). Serum concentrations of 60 cytokines were profiled by Luminex and ELISA, with comparisons made both between ESLD and HC, and across ESLD aetiologies (alcohol-related, NAFLD, viral hepatitis, other). In vitro, primary human myotubes (from non-ESLD aged donors, NRES #16/SS/0172) were treated with 10% ESLD or HC plasma (24 h, n=6 per group) followed by RNA sequencing (BGI Genomics). Differentially expressed genes (p<0.05, fold-change >1.5) were identified via Qlucore and DESeq2, and pathway analysis performed using Ingenuity (Qiagen). The impact of physiological concentrations of candidate cytokines (IL-1, GDF-15, HGF) on myotube thickness, differentiation and mitochondrial function was assessed by immunofluorescence microscopy, RT-qPCR and metabolic flux assays. ResultsIn ESLD muscle, 387 and 225 genes were significantly up- and downregulated compared to HC respectively, with cellular senescence identified as a top dysregulated function. Upstream regulator analysis predicted activation of hepatocyte growth factor (HGF) and interleukin-1 signalling. Subgroup analysis revealed distinct transcriptomic profiles based on disease aetiology. Serum profiling identified 15 cytokines significantly elevated (p<0.05) and 5 reduced (p<0.05) in ESLD, including increased HGF and reduced interleukin-1 receptor antagonist. Stratified analysis also revealed aetiology specific cytokine profiles, with only GDF-15 significantly (P<0.0001) elevated in all groups. 24h ESLD plasma treatment induced 423 differentially expressed genes in human myotubes, which were again associated with significant activation of senescence pathways, with IL-1 identified as a key upstream driver. In vitro, IL-1, GDF-15, and HGF significantly reduced myotube thickness, nuclear fusion index and perturbed metabolism (Increased glycolysis, impaired oxidative phosphorylation). ConclusionsCollectively, these findings suggest that sarcopenia in ESLD is driven by aetiology-specific mechanisms, highlighting the potential for targeted therapies to improve muscle mass and function.

molecular biology↗
bioRxiv2025

High-salt diet modulates endocrine regulation between cortisol and FGF23

Excessive dietary salt intake is a global health concern, affecting cardiovascular, renal, and bone health. While the renin-angiotensin-aldosterone system (RAAS) is a known regulator of dietary salt-induced hormonal responses, the impact of adrenal cortisol remains unclear. Here, we performed a retrospective analysis in individuals (n=292) consuming a random diet. Dietary salt intake positively correlated with urinary cortisol and inversely correlated with plasma fibroblast growth factor 23 (FGF23), a bone-derived hormone regulating phosphate and vitamin D homeostasis. Controlled salt diets in healthy individuals confirmed a dose-dependent increase in urinary cortisol and suppression of plasma FGF23. In mice, oral corticosterone, a cortisol analogue, reduced circulating FGF23 levels. RNA-seq analysis of corticosterone-treated MC3T3 osteoblasts identified suppression of FGF23 via glucocorticoid receptor activation, anti-inflammatory pathways, and reduced osteoblast activity. Our findings reveal a novel endocrine cascade where high salt intake elevates cortisol and suppresses FGF23, with potential implications for bone, kidney, and cardiovascular health. SIGNIFICANCE STATEMENTExcessive dietary salt intake is a global health concern with poorly understood hormonal consequences beyond the renin-angiotensin-aldosterone system. Here, we identify a novel endocrine cascade in which high salt intake elevates cortisol signaling and suppresses fibroblast growth factor 23 (FGF23), a bone-derived hormone central to phosphate and vitamin D homeostasis. These findings are supported by a human cohort on random diets, a controlled dietary salt intervention, and corticosterone experiments in mice and osteoblasts. Mechanistically, cortisol suppresses FGF23 via glucocorticoid receptor activation, anti-inflammatory signaling, and repression of osteoblast activity. These findings have potential implications for bone, kidney, and cardiovascular health, and suggest that dietary salt intake may influence the clinical interpretation of cortisol and FGF23 measurements.

physiology↗