Cardiac Troponin I-Interacting Kinase Affects Cardiomyocyte S-Phase Activity but Not Cardiomyocyte Proliferation

Area of Science:

• Cardiovascular Biology
• Genetics
• Regenerative Medicine

Background:

• Identifying genetic factors influencing cardiomyocyte cell cycle reentry is crucial for developing cardiac regeneration therapies.
• Significant differences in cardiomyocyte S-phase activity were observed between C57Bl6/NCR (B6N) and DBA/2J (D2J) mice following myocardial infarction.

Purpose of the Study:

• To identify genetic variants that modulate cardiomyocyte cell cycle progression after cardiac injury.
• To pinpoint the specific gene responsible for differential S-phase activity in mouse models of myocardial infarction.

Main Methods:

• Monitoring cardiomyocyte cell cycle activity using nucleoside incorporation (BrdU/EdU) and a transgenic reporter in D2J, F1, and backcross mice.
• Employing genome-wide quantitative trait locus (QTL) analysis, genetic mapping, exome sequencing, and RNA sequencing to identify candidate genes.

Main Results:

• (D2J×B6N)-F1 mice showed a 14-fold increase in cardiomyocyte S-phase activity compared to D2J mice.
• QTL analysis localized the responsible gene to chromosome 3; further analysis identified troponin I-interacting kinase (Tnni3k) as a key candidate.
• Tnni3k expression in B6N but not D2J hearts correlated with elevated S-phase activity, and its transgenic expression in D2J mice replicated this phenotype.

Conclusions:

• Tnni3k expression significantly increases cardiomyocyte S-phase activity following cardiac injury.
• This finding highlights Tnni3k as a critical regulator of cardiomyocyte proliferation and a potential target for cardiac regeneration therapies.