Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle

<p>Succinate is released by skeletal muscle during exercise and activates <em>SUCNR1</em>/GPR91. Signaling of SUCNR1 is involved in cell-cell communication in skeletal muscle. However, the specific cell types responding to succinate and the directionality of communication are unclear. <em>De novo</em> analysis of transcriptomic datasets demonstrated that <em>SUCNR1</em> mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, <em>SUCNR1</em> mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, <em>SUCNR1</em> mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of <em>SUCNR1</em> mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to <em>SUCNR1</em> agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle.</p>