Exploring the role of chemerin in skeletal muscle phenotype in those with kidney disease

INTRODUCTION: People with chronic kidney disease (CKD) often experience poor muscle quality and elevations in skeletal muscle wasting and dysfunction, contributing to a reduced quality of life and an increased risk of morbidity and mortality. The adipokine chemerin is associated with CKD progression and is involved in inflammatory-related signalling processes. With chronic inflammation recognised as a driving factor in uraemic sarcopenia, we aimed to investigate the potential role of chemerin as a uraemic toxin in CKD and identify the mechanisms of action to elucidate therapeutic opportunities in uraemic sarcopenia. METHODS: To achieve this, we used a holistic approach utilising in-vivo, ex-vivo and in-vitro analyses in order to explore the link between chemerin and skeletal muscle in the context of CKD. Chemerin levels from EDTA-plasma and urine samples were quantified via ELISA on basal samples from those across the kidney disease continuum. Chemerin levels were correlated with eGFR and measures of body composition, physical performance, muscle mass, and muscle quality. A sub-set of participants from each group underwent skeletal muscle biopsies, and samples were processed for gene and protein analysis, or cells extracted for in-vitro experimentation. For in-vitro experiments, human-derived muscle cells (HDMCs) isolated from CKD or aged-matched controls (CON) were differentiated and subsequently exposed to a dose-response of Chemerin. Subsequent experiments used the CMKLR1 selective inhibitor to seek to identify a mechanism of action. RESULTS: = 0.043, p = 0.057). The expression of Chemerin and its proposed receptor of interest CMKLR1 was detected in skeletal muscle. In-vitro analysis showed that the exposure of CKD-derived muscle cells to chemerin induced a significant inflammatory response (IL-6 p < 0.001; CCL-2 p = 0.0215), which was halved using the CMKLR1 receptor inhibitor αNETA (IL-6 p < 0.001; CCL-2 p < 0.001). CONCLUSION: We report that chemerin is a uraemic toxin in those with CKD and may contribute to poorer muscle quality in these people. Chemerin can moderate indicators of inflammation within HDMCs via the activation of CMKLR1 and warrants further investigations to validate it as a potential new therapeutic target to alleviate the symptoms of uraemic sarcopenia.