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

作者：William Joyce, Kai He, Mengdie Zhang, Samuel Ogunsola, Xini Wu, K. Joseph, David Bogomolny, Wenhua Yu, Mark S. Springer, Jiuyong Xie, Anthony V. Signore, Kevin L. Campbell · 发表于：Science · 年份：2024 · DOI：10.1126/science.adi8146 · 被引用次数：17 · 研究领域：Cardiomyopathy and Myosin Studies、RNA and protein synthesis mechanisms、RNA Research and Splicing

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.