Soluble RAGE and skeletal muscle tissue RAGE expression profiles in lean and obese young adults across differential aerobic exercise intensities

Abstract

Nearly 40% of Americans have obesity and are at increased risk for developing type 2 diabetes. Skeletal muscle is responsible for >80% of insulin-stimulated glucose uptake which is attenuated by the inflammatory milieu of obesity and augmented by exercise. The Receptor for Advanced Glycation Endproducts (RAGE) is an inflammatory receptor directly linking metabolic dysfunction with inflammation. Circulating soluble isoforms of RAGE (sRAGE) formed either by proteolytic cleavage (cRAGE) or alternative splicing (esRAGE) act as decoys for RAGE ligands thereby counteracting RAGE-mediated inflammation. PURPOSE We aimed to determine if RAGE expression or alternative splicing of RAGE is altered by obesity in muscle, and whether acute aerobic exercise (AE) modifies RAGE and sRAGE. METHODS Young (20-34y) participants without (n=17; BMI: 22.6±2.6 kg/m2) and with obesity (n=7; BMI: 32.8±2.9 kg/m2) performed acute aerobic exercise (AE) at 40, 65 or 80% of VO2Max (mL/kg/min) on separate visits. Blood was taken before and 30 minutes after each exercise bout. Muscle biopsy samples were taken before, 30 minutes, and 3 hours after the 85% VO2Max exercise bout. RESULTS Individuals with obesity had higher total RAGE and esRAGE mRNA and RAGE protein (p<0.0001). In addition, RAGE and esRAGE transcripts correlated to transcripts of the NF-κB subunit P65 (p<0.05). There was no effect of exercise on total RAGE or esRAGE transcripts, or RAGE protein (p>0.05) and AE tended to decrease circulating sRAGE. CONCLUSIONS RAGE expression is exacerbated in skeletal muscle with obesity, which may contribute to the development of skeletal muscle metabolic dysfunction such as insulin resistance.

Effects of acute aerobic exercise on circulating sTLR and sRAGE profiles in normal‐ and abnormal‐glucose‐tolerant individuals

“…To our knowledge, this is the first report on circulating sTLR and sRAGE levels in individuals with apparent abnormal glucose regulation following acute aerobic exercise. However, we recently demonstrated that while young individuals with obesity have higher muscle RAGE protein expression, they do not appear to exhibit different circulating sRAGE levels (Miranda et al, 2023). Furthermore, muscle RAGE expression was strongly related to HOMA-IR, in disagreement with findings presented here.…”

ATP-Binding Cassette Family C member 1 constrains metabolic responses to high-fat diet in male mice

“…It is worthy of note that bulk RNA-seq can have some pitfalls when the heterogeneity of the tissues is high (Denninger, et al 2022; Li and Wang 2021; Noureen, et al 2022). An expansion of adipose tissue due to HFD exposure has been shown not only to change the cell profile in adipose tissue by increasing proinflammatory cells, but also in skeletal muscle (Chait and den Hartigh 2020; Fuster, et al 2016; Miranda, et al 2023; Morgan, et al 2020).…”