In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.

为了响应运动过程中的骨骼肌收缩，旁分泌因子协调组织重塑，这是这种健康适应的基础。在这里，我们描述了一种在运动时启动肌肉重塑的 pH 感应代谢物信号。在小鼠和人类中，锻炼骨骼肌会将线粒体代谢物琥珀酸释放到局部间质和循环中。琥珀酸的选择性分泌是由其瞬时质子化促进的，这种质子化发生在肌肉细胞酸化时。在质子化的一元羧酸形式中，琥珀酸盐是单羧酸盐转运蛋白 1 的转运底物，可促进 pH 门控释放。分泌后，琥珀酸通过肌肉组织中非肌原纤维细胞中的同源受体 SUCNR1 发出信号，以控制肌肉重塑转录程序。这种琥珀酸-SUCNR1 信号是运动训练对肌肉神经支配、肌肉基质重塑和肌肉力量的旁分泌调节所必需的。总之，我们在肌肉中定义了一种生物能量传感器，它利用细胞内的 pH 值和琥珀酸来协调组织对运动的适应。