Key result
Pseudoexonization of TNNI3 exon 3 yields truncated troponin I to facilitate ultra-rapid mammalian heart rates.
The evolutionary loss of TNNI3 exon 3 in tachycardic mammals suggests that therapeutically inducing alternative splicing of human TNNI3 could offer a novel strategy to improve diastolic function in heart failure.
Mammalian cardiac troponin I (cTnI) contains a highly conserved N-terminal extension harboring protein kinase A targets (Ser 23/24 ) which are phosphorylated during ß-adrenergic stimulation to increase cardiomyocyte relaxation rate. Here, 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 min -1 ). We further reveal alternative exon 3 splicing in distantly related bat families and that both exon 3 - and exon 3 + cTnI isoforms are incorporated into cardiac myofibrils. Finally, exon 3 of human TNNI3 is 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.
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Joyce et al. (2023) studied this question. Evolutionary pseudoexonization and alternative splicing of TNNI3 exon 3 vs. Intact and constitutively expressed TNNI3 exon 3 was evaluated on Expression and PKA phosphorylatability of cTnI N-terminal extension. Shrews and moles independently evolved a truncated cardiac troponin I through pseudoexonization of TNNI3 exon 3 to facilitate rapid heart rates without chronic adrenergic stimulation.
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