Abstract
During perinatal development, myocardial proteins often undergo isoform switch from fetal to neonatal/adult type. This is also true for titin, a giant elastic protein in sarcomere that defines a myocardial passive stiffness and thus ventricular filling in diastole. In mammalian heart, the long and compliant N2BA isoform expressed in fetus is replaced by short and stiff N2B isoform in neonate/ adult, limiting the distensibility of the latter heart. Both are generated by alternative splicing from the single titin gene. Recently Rbm20 was identified as a main regulator of titin splicing, but its role in the perinatal titin switch is unknown. In mammals, the onset of breathing at birth leads to abrupt elevation of oxygen. In this study, we focused on the role of Rbm20 in the perinatal titin switch, and its regulation by oxygen. First we established the system to detect MDa-sized titin, and confirmed the perinatal switch did occur. Exposure of fetal cardiomyocytes to atmospheric oxygen mimicked the isoform shift from N2BA to N2B, suggesting the elevated oxygen at birth is an upstream cue. We are now exploring Rbm20 activity around birth, and its potential as an oxygen-sensing molecule.
