Succinate activation of SUCNR1 promotes skeletal muscle endurance, protein synthesis, and fiber type remodeling, while contributing to pathological cardiac hypertrophy and ischemia-reperfusion injury through multiple signaling pathways.
This article reviews the physiological and pathological mechanisms of succinic acid receptor 1 (SUCNR1) in skeletal, cardiac, and vascular smooth muscle, with the aim of systematizing the multifunctional roles of this receptor in muscle tissues and evaluating its value as a potential target for intervention in metabolic, cardiovascular, and inflammatory diseases. By reviewing the discovery history, structural features and ligand selectivity of SUCNR1, we found that SUCNR1 can sense local high level of succinate in a manner of low-affinity, high-selectivity, and may regulate energy metabolism and inflammatory diseases through multiple signaling axes, such as Gαi/q-PLCβ-Ca 2+, Akt/mTOR, and ERK1/2, there by precisely regulating body energy metabolism and proteostasis. In skeletal muscle, a ″state-dependent expression″ model was proposed by integrating contradictory experimental data. In resting healthy myofibers, SUCNR1 is hardly expressed, when succinate affects resident macrophages, satellite cells and vascular endothelial cells mainly through paracrine effects. However, under stress such as differentiation, exercise or injury, myofibers re-express SUCNR1 and are able to respond directly to succinate. Further studies revealed that chronic succinate supplementation promotes the conversion of fast to slow muscle fibers through the SUCNR1/PLCβ/Ca 2+-NFAT signaling pathway, which in turn improves muscle endurance. On the other hand, acute administration enhances oxidative phosphorylation and myosin synthesis through the Ca2+-ERK/Akt/mTOR signaling axis, which results in a rapid increase in muscle strength. In addition, satellite cell-specific knockdown experiments further confirmed that the SUCNR1-PKCη-p38α signaling pathway is essential for exercise-induced muscle hypertrophy and neuromuscular junction remodeling. In the myocardium, a ″double-edged sword″ role of SUCNR1 was proposed in pathological cardiac hypertrophy and ischemia-reperfusion injury (IRI). In pathological hypertrophy, pressure loading or hypoxia causes accumulation of succinate, which then activates the PI3K/Akt and MEK/ERK signaling pathways through SUCNR1-Gi/q coupling, inducing the expression of hypertrophic genes, such as ANP and BNP to promote cardiomyocyte hypertrophy; at the same time, succinate promotes the transformation of macrophages to a pro-inflammatory phenotype by activating SUCNR1, which in turn triggers a series of inflammatory reactions. These inflammatory reactions interact with the hypertrophy process of cardiomyocytes to form a positive feedback mechanism to promote the continuous development of myocardial hypertrophy. In the IRI scenario, succinate was oxidized by SDH upon reperfusion, which in turn drove the ROS burst, increased intracellular Ca2+ concentration via SUCNR1, activated PKA, and triggered the phosphorylation of mitochondrial fission protein MFF, leading to mitochondrial fragmentation and apoptotic cell death. Inhibition of SDH or blockade of SUCNR1 could effectively attenuate ROS and Ca 2+ overload and significantly reduce infarct size. In the vascular smooth muscle and atherosclerosis section, the mechanism of action of SUCNR1 was explored by comparing the two opposing evidence of ″pro-inflammatory″ and ″protective″ effects. On the one hand, succinate activated the NF-κB, HIF-1α, and RAS-Ang II axes by binding to SUCNR1, promoting phenotypic transformation, foam cell formation, and plaque inflammation in vascular smooth muscle cells. The systemic knockout SUCNR1 model did not show significant lesion differences in low-fat or early high-fat stages, suggesting that the action of SUCNR1 is stage- and microenvironment-dependent. Recent studies reveal that SUCNR1 can amplify vascular endothelial inflammation by enhancing endoplasmic reticulum stress and increasing endoplasmic reticulum-mitochondrial contact to lead to mitochondrial injury, and activating the cGAS-STING signaling pathway, offering a new target for atherosclerosis intervention. Based on the above, we put forward three suggestions: first, in terms of clinical testing, the dynamic changes of plasma succinate should be detected instead of focusing only on the concentration at single time point, and the expression of SUCNR1 should be detected in conjunction with muscle biopsy to differentiate between physiological adaptation and pathological stress states. Second, SUCNR1 modulators with tissue preference should be developed, specifically skeletal muscle-selective agonists for hypokinesia and sarcopenia, and myocardial/vascular-selective antagonists for myocardial hypertrophy, heart failure, and IRI. Finally, in terms of therapeutic strategies, it is recommended to co-target SDH, Ca2+ channels, or the endoplasmic reticulum stress pathway, and to devise a multidimensional synergistic strategy of metabolic-immunological-mechanical (MIM) and immunological-mechanical (MIM) to overcome the possible compensatory side effects of single blockade of SUCNR1. Future studies need to further validate the temporal and spatial dynamics of the succinate-SUCNR1 axis in human cohorts and clarify the cell-type-specific transcriptional regulatory networks with the help of single-cell multi-omics technology in order to realize precise intervention in related diseases.
Yan et al. (Thu,) conducted a review in Muscle pathophysiology including skeletal muscle, cardiac hypertrophy, ischemia-reperfusion injury, and atherosclerosis. Succinate activation of SUCNR1 promotes skeletal muscle endurance, protein synthesis, and fiber type remodeling, while contributing to pathological cardiac hypertrophy and ischemia-reperfusion injury through multiple signaling pathways.