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

Abstract

Succinate is released by skeletal muscle during exercise and activates SUCNR1/GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that SUCNR1 mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, SUCNR1 mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, SUCNR1 mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of SUCNR1 mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 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.

Molecular insights of exercise therapy in disease prevention and treatment

“… 48 , 49 For instance, plasma levels of succinate increase substantially in response to acute exercise 50 and paracrine signaling from skeletal muscle tissue to non-myofibrillar muscle-resident cell types such as immune and endothelial cells was shown to confer skeletal muscle and extracellular matrix remodeling. 51 – 53 In view of the endocrine mobilization of succinate, adaptions in other, more distant target tissues were also described. 54 , 55 …”

“…In summary, skeletal muscle is stimulated by various exerkines in an autocrine, paracrine, and/or endocrine fashion and the structural and functional adaptions induced by exerkine signaling range from classic endurance adaptions, 95 , 146 , 148 , 149 , 152 via anti-sarcopenic effects, 51 , 52 , 152 , 166 through to anti-diabetic and metabolic effects. 145 , 147 , 148 , 150 , 151 , 153 , 154 Besides mechanistic insights into the molecular foundations of exercise adaptions, these studies highlight how the knowledge of specific exerkine receptor signaling in a target tissue can be transferred to potential other target tissues that express the same exerkine receptor.…”