《生命科学》 2026, 38(1): 82-98
SUCNR1在肌肉生理病理中的作用及机制
摘 要：
细胞外琥珀酸被认为是一种重要的信号代谢产物。它与其受体SUCNR1相互作用，激活多种细胞信号通
路，从而调控机体的日常体力活动、剧烈运动以及其他生理应激（如缺氧）。SUCNR1在肾脏、肝脏、心肌、视网膜等多种组织中广泛表达。近年来的研究发现，SUCNR1通过Ca2+、Akt和ERK等信号通路，在骨骼肌肥大、纤维类型转化、病理性心肌肥大以及血管平滑肌的收缩与舒张等生理和病理过程中发挥独特作用。本文介绍了SUCNR1的结构与分布特征，并重点探讨了其在骨骼肌、心肌和平滑肌中的作用机制与功能，旨在为相关疾病的防治提供新的思路和潜在策略。
通讯作者：衣雪洁 , Email:Yixuejie8387@163.com
Abstract:
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-Ca2+, 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/Ca2+-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 Ca2+ 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.
Communication Author：YI Xue-Jie , Email:Yixuejie8387@163.com
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