Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea, 25354.
Department of International Agricultural Technology, Graduate School of International Agricultural Technology, Pyeongchang, Seoul National University, Republic of Korea, 25354.
Proc Natl Acad Sci U S A. 2024 Jan 23;121(4):e2308960121. doi: 10.1073/pnas.2308960121. Epub 2024 Jan 17.
Metabolic disorders are characterized by an imbalance in muscle fiber composition, and a potential therapeutic approach involves increasing the proportion of oxidative muscle fibers. Prokineticin receptor 1 (PROKR1) is a G protein-coupled receptor that plays a role in various metabolic functions, but its specific involvement in oxidative fiber specification is not fully understood. Here, we investigated the functions of PROKR1 in muscle development to address metabolic disorders and muscular diseases. A meta-analysis revealed that the activation of PROKR1 upregulated exercise-responsive genes, particularly nuclear receptor subfamily 4 group A member 2 (NR4A2). Further investigations using ChIP-PCR, luciferase assays, and pharmacological interventions demonstrated that PROKR1 signaling enhanced NR4A2 expression by Gs-mediated phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) in both mouse and human myotubes. Genetic and pharmacological interventions showed that the PROKR1-NR4A2 axis promotes the specification of oxidative muscle fibers in both myocytes by promoting mitochondrial biogenesis and metabolic function. Prokr1-deficient mice displayed unfavorable metabolic phenotypes, such as lower lean mass, enlarged muscle fibers, impaired glucose, and insulin tolerance. These mice also exhibited reduced energy expenditure and exercise performance. The deletion of Prokr1 resulted in decreased oxidative muscle fiber composition and reduced activity in the Prokr1-CREB-Nr4a2 pathway, which were restored by AAV-mediated Prokr1 rescue. In summary, our findings highlight the activation of the PROKR1-CREB-NR4A2 axis as a mechanism for increasing the oxidative muscle fiber composition, which positively impacts overall metabolic function. This study lays an important scientific foundation for the development of effective muscular-metabolic therapeutics with unique mechanisms of action.
代谢紊乱的特征是肌肉纤维组成失衡，一种潜在的治疗方法是增加氧化型肌肉纤维的比例。促动力蛋白受体 1（PROKR1）是一种 G 蛋白偶联受体，在各种代谢功能中发挥作用，但它在氧化型纤维特化中的具体作用尚不清楚。在这里，我们研究了 PROKR1 在肌肉发育中的功能，以解决代谢紊乱和肌肉疾病问题。荟萃分析显示，PROKR1 的激活上调了运动反应基因，特别是核受体亚家族 4 组 A 成员 2（NR4A2）。进一步的研究使用 ChIP-PCR、荧光素酶测定和药理学干预表明，PROKR1 信号通过 Gs 介导的环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）磷酸化增强 NR4A2 的表达，这在小鼠和人类肌管中均如此。遗传和药理学干预表明，PROKR1-NR4A2 轴通过促进线粒体生物发生和代谢功能，促进氧化型肌肉纤维在肌细胞中的特化。Prokr1 缺陷型小鼠表现出不利的代谢表型，如瘦体重降低、肌肉纤维增大、葡萄糖和胰岛素耐量受损。这些小鼠还表现出能量消耗和运动性能降低。Prokr1 的缺失导致氧化型肌肉纤维组成减少，Prokr1-CREB-Nr4a2 通路活性降低，通过 AAV 介导的 Prokr1 挽救得到恢复。总之，我们的研究结果强调了激活 PROKR1-CREB-NR4A2 轴作为增加氧化型肌肉纤维组成的机制，这对整体代谢功能有积极影响。这项研究为开发具有独特作用机制的有效的肌肉代谢治疗方法奠定了重要的科学基础。
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