Parallel genetic excisions of the cardiac troponin I N-terminal extension in tachycardic mammals

Abstract

AbstractMammalian cardiac troponin I (cTnI) contains a highly conserved N-terminal extension harboring protein kinase A targets (Ser23/24) which are phosphorylated during ß-adrenergic stimulation to increase cardiomyocyte relaxation rate. Here, we show that the Ser23/24encoding exon 3 ofTNNI3was pseudoexonized multiple times in shrews and moles to mimic Ser23/24phosphorylation without adrenergic stimulation, thereby facilitating the evolution of exceptionally high resting heart rates (∼1000 beats min-1). We further reveal alternative splicing ofTNNI3exon 3 in distantly related bat families with both full-length and truncated cTnI isoforms being incorporated into cardiac myofibrils. Finally, exon 3 of humanTNNI3is shown to exhibit a relatively low splice strength score, offering an evolutionarily informed strategy to excise this exon to improve diastolic function during heart failure.One-Sentence SummaryShrews, moles and bats independently evolved a truncated cardiac troponin I to facilitate rapid heart rates without chronic adrenergic stimulation.