Mammalian cardiac troponin I (cTnI) contains a highly conserved amino-terminal extension harboring protein kinase A targets [serine-23 and -24 (Ser 23/24 )] 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 Ser 23/24 -encoding exon 3 of TNNI3 was pseudoexonized multiple times in shrews and moles to mimic Ser 23/24 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.

中文翻译：

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高心率哺乳动物分支中调节性心肌肌钙蛋白 I 延伸的基因切除


哺乳动物心肌肌钙蛋白 I （cTnI） 包含一个高度保守的氨基末端延伸，其中含有蛋白激酶 A 靶标 [丝氨酸-23 和 -24 （Ser 23/24 ）]，这些靶标在 β-肾上腺素能刺激过程中被磷酸化，通过增加心肌细胞松弛率来捍卫舒张期充盈。在这项工作中，我们表明 TNNI3 的 Ser 23/24 编码外显子 3 在鼩鼱和鼹鼠中被多次伪外显子化，以模拟 Ser 23/24 磷酸化而没有肾上腺素能刺激，促进异常高的静息心率（~1000 次/分钟）的进化。我们进一步揭示了远亲蝙蝠家族中的选择性外显子 3 剪接，并证实两种 cTnI 剪接变体都掺入心肌原纤维中。由于人 TNNI3 的外显子 3 表现出相对较低的剪接强度评分，我们的研究结果提供了一种进化知情的策略来切除该外显子以改善心力衰竭期间的舒张功能。