小柯机器人

加拿大曼尼托巴大学Kevin L. Campbell等研究人员合作实现，在高心率哺乳动物类群中调控型心脏肌钙蛋白I扩展的基因切除。相关论文发表在2024年9月27日出版的《科学》杂志上。

研究人员表示，哺乳动物心脏肌钙蛋白I（cTnI）包含一个高度保守的氨基末端扩展，含有蛋白激酶A靶点[丝氨酸-23和-24（Ser^23/24）]。其在β-肾上腺素刺激下被磷酸化，进而通过增加心肌细胞的放松速率来保护舒张期充盈。

研究人员展示了TNNI3的Ser^23/24编码外显子3在鼩鼱和鼹鼠中被多次假外显子化，以便在没有肾上腺刺激的情况下模拟Ser^23/24磷酸化，从而促进了异常高的静息心率（约1000次/分钟）的演化。

研究人员进一步揭示了远缘蝙蝠科中的外显子3的可变剪接，并确认这两种cTnI剪接变体均被纳入心肌细胞肌原纤维中。由于人类TNNI3的外显子3显示出相对较低的剪接强度评分，该发现提供了一种基于演化的信息策略来切除该外显子，从而改善心力衰竭期间的舒张功能。

附：英文原文

Title: Genetic excision of the regulatory cardiac troponin I extension in high–heart rate mammal clades

Author: William Joyce, Kai He, Mengdie Zhang, Samuel Ogunsola, Xini Wu, Kelvin T. Joseph, David Bogomolny, Wenhua Yu, Mark S. Springer, Jiuyong Xie, Anthony V. Signore, Kevin L. Campbell

Issue&Volume: 2024-09-27

Abstract: Mammalian cardiac troponin I (cTnI) contains a highly conserved amino-terminal extension harboring protein kinase A targets [serine-23 and -24 (Ser23/24)] that are phosphorylated during β-adrenergic stimulation to defend diastolic filling by means of an increased cardiomyocyte relaxation rate. In this work, we show that the Ser23/24-encoding exon 3 of TNNI3 was pseudoexonized multiple times in shrews and moles to mimic Ser23/24 phosphorylation without adrenergic stimulation, facilitating the evolution of exceptionally high resting heart rates (~1000 beats per minute). We further reveal alternative exon 3 splicing in distantly related bat families and confirm that both cTnI splice variants are incorporated into cardiac myofibrils. Because exon 3 of human TNNI3 exhibits a relatively low splice strength score, our findings offer an evolutionarily informed strategy to excise this exon to improve diastolic function during heart failure.

DOI: adi8146

Source: https://www.science.org/doi/10.1126/science.adi8146