Innervating sympathetic neurons regulate heart size and the timing of cardiomyocyte cell cycle withdrawal

• Published in: The Journal of physiology Vol. 593; no. 23; pp. 5057 - 5073
• Main Authors: Kreipke, R. E., Birren, S. J.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.12.2015; John Wiley and Sons Inc
• Subjects: Adrenergic Neurons - physiology; Animals; Cardiomyocytes; Cell Cycle; Cells, Cultured; Cellular Physiology; Female; Heart; Heart - growth & development; Heart - innervation; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Male; Maternal, Fetal and Neonatal Physiology; Molecular and cellular; Myeloid Ecotropic Viral Integration Site 1 Protein; Myocardium - pathology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - physiology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neurons; Organ Size; Rats; Rats, Sprague-Dawley; Research Paper; Sympathetic Nervous System - cytology; Sympathetic Nervous System - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP270917

Key points Cardiomyocytes withdraw from the cell cycle late in prenatal and early in postnatal life and subsequent heart growth occurs via cellular hypertrophy. The signals regulating this transition remain unknown. Lesion of the neonatal sympathetic nervous system results in decreased heart size. In vitro investigations show that sympathetic neurons delay cardiomyocyte maturation and cell cycle withdrawal. Early sympathetic innervation may contribute to the determination of adult heart size by regulating the total number of cardiomyocytes via regulation of the proliferative/hypertrophic transition. Early perturbations of sympathetic structure or function could have long‐term effects on adult heart function. Sympathetic drive to the heart is a key modulator of cardiac function and interactions between heart tissue and innervating sympathetic fibres are established early in development. Significant innervation takes place during postnatal heart development, a period when cardiomyocytes undergo a rapid transition from proliferative to hypertrophic growth. The question of whether these innervating sympathetic fibres play a role in regulating the modes of cardiomyocyte growth was investigated using 6‐hydroxydopamine (6‐OHDA) to abolish early sympathetic innervation of the heart. Postnatal chemical sympathectomy resulted in rats with smaller hearts, indicating that heart growth is regulated by innervating sympathetic fibres during the postnatal period. In vitro experiments showed that sympathetic interactions resulted in delays in markers of cardiomyocyte maturation, suggesting that changes in the timing of the transition from hyperplastic to hypertrophic growth of cardiomyocytes could underlie changes in heart size in the sympathectomized animals. There was also an increase in the expression of Meis1, which has been linked to cardiomyocyte cell cycle withdrawal, suggesting that sympathetic signalling suppresses cell cycle withdrawal. This signalling involves β‐adrenergic activation, which was necessary for sympathetic regulation of cardiomyocyte proliferation and hypertrophy. The effect of β‐adrenergic signalling on cardiomyocyte hypertrophy underwent a developmental transition. While young postnatal cardiomyocytes responded to isoproterenol (isoprenaline) with a decrease in cell size, mature cardiomyocytes showed an increase in cell size in response to the drug. Together, these results suggest that early sympathetic effects on proliferation modulate a key transition between proliferative and hypertrophic growth of the heart and contribute to the sympathetic regulation of adult heart size.