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

• 成果类型: Article
• 署名作者: Joyce, William; He, Kai; Zhang, Mengdie; Ogunsola, Samuel; Wu, Xini; Joseph, Kelvin T.; Bogomolny, David; Yu, Wenhua; Springer, Mark S.; Xie, Jiuyong; Signore, Anthony V.; Campbell, Kevin L.
• 署名单位: Aarhus University; University of Manchester; Guangzhou University; University of Manitoba; University of Manitoba; University of California System; University of California Riverside; Centro Nacional de Investigaciones Cardiovasculares (CNIC)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12629
• DOI: 10.1126/science.adi8146
• 发表日期: 2024-09-27
• 页码: 1466-1471
• 关键词: n-terminal extension; striated-muscle; phosphorylation; metabolism; proteins; binding; mole; temperature; sensitivity; myocardium

摘要

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 beta-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 (similar to 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.