Environmental disruption alters circadian clock gene expression, increasing the risk of adverse cardiac events and suggesting cardiomyocyte-specific circadian responses to external stimuli. Analyses of previously reported transcriptomic data revealed increased expression of Titin-cap (Tcap) in adult compared to embryonic myocytes and identified myosin light chain 2 (Myl2) as clock-controlled. Given cardiac sarcomeric roles of the encoded proteins, we hypothesized that extracellular cues driving postnatal cardiac maturation and hypertrophy influence time-of-day Tcap and Myl2 expression. Tcap induction was concomitant with neonatal myocyte binucleation, fetal gene suppression, and increased heart weight during the early phase of cardiac growth. Since norepinephrine stimulates β-adrenergic and α-adrenergic receptors, the latter driving clock-controlled transcriptional remodeling, phase‑response curves of the β‑adrenergic agonist isoproterenol (ISO) following α-adrenergic stimulation with phenylephrine (PE) were performed on neonatal rat ventricular myocytes (NRVM), revealing periodic myocyte hypertrophy and TCAP protein expression. PE entrenched ISO-mediated Tcap suppression, to which oscillatory Per2 and Myl2 transcription was impervious. Differential NRVM culture density revealed biomass-dependent changes in Per2 and Tcap transcription and hypertrophy timing. Hypoxia initiated myocyte atrophy and Bmal1-dependent Tcap transcription, reflected in decreased heart weight and increased Tcap expression in hypoxic neonatal rat hearts. Tcap depletion impaired Bmal1 and fetal hypertrophic gene expression, compromised hypoxia-mediated Myl2 transcriptional suppression, and aggravated hypoxia-induced atrophy. In summary, Tcap and Myl2 are circadian genes differentially influenced by environmental factors, including adrenergic stimulation, paracrine signaling, and O2 tension during postnatal cardiac maturation. These findings have implications for the distinct regulation of myocyte growth and maturation, by external cues during the postnatal period.
