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Abstract 137: The Role of TNNI3K in Adult Mammalian Heart Regeneration


 Adult mammalian heart regenerative capacity is thought to be extremely limited. All fetal and newborn mouse cardiomyocytes are mononuclear and diploid, and most become polyploid during the first postnatal week. Our lab showed that mononucleated diploid cardiomyocytes (MNDCMs) retain regenerative capacity, and that the percentage of this subpopulation in the adult mouse heart is variable across strains and correlated with the regeneration capacity of mouse heart. We reported cardiac troponin I-interacting kinase (TNNI3K), a novel cardiac specific gene, to be a key regulator of MNDCM frequency. Nonetheless, a detailed mechanism of how
 Tnni3k
 regulates MNDCM frequency is still lacking. TNNI3K is a MAPKKK by sequence, but no change in MAPK signaling pathways (p38, ERK1/2, JNK) occurs in
 Tnni3k
 knock-out mice. To distinguish whether
 Tnni3k
 plays a kinase role, we created a mouse line harboring the kinase-dead mutant of
 Tnni3k (Tnni3k-k489r)
 , which recapitulates the high MNCM frequency of
 Tnni3k
 knock-out mice. Engineered
 Tnni3k
 truncations in mice yield no stable protein, and these mice also show a high MNCM frequency. Interestingly, we found that naked mole-rat (
 Heterocephalus glaber
 ) has a
 Tnni3k
 truncation mutation, doesn't express a stable TNNI3K protein, and has a high level of MNCM frequency and cardiomyocyte polyploidy. These results indicate that
 Tnni3k
 may influence cardiomyocyte karyokinesis and cytokinesis across mammalian species. We also found that several human
 TNNI3K
 polymorphisms compromise kinase activity, which may influence variation in MNDCM frequency and heart regenerative capacity in the human population.
