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

Science. 2024 Sep 27;385(6716):1466-1471. doi: 10.1126/science.adi8146. Epub 2024 Sep 26.

Abstract

Mammalian cardiac troponin I (cTnI) contains a highly conserved amino-terminal extension harboring protein kinase A targets [serine-23 and -24 (Ser23/24)] 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 Ser23/24-encoding exon 3 of TNNI3 was pseudoexonized multiple times in shrews and moles to mimic Ser23/24 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.

MeSH terms

  • Alternative Splicing*
  • Animals
  • Exons*
  • Heart Rate* / genetics
  • Humans
  • Myocardial Contraction* / genetics
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • Myofibrils / metabolism
  • Phosphorylation
  • Phylogeny
  • Serine / genetics
  • Serine / metabolism
  • Troponin I* / classification
  • Troponin I* / genetics
  • Troponin I* / metabolism

Substances

  • Serine
  • TNNI3 protein, human
  • Troponin I