Augmented Cardiac Growth Hormone Signaling Contributes to Cardiomyopathy Following Genetic Disruption of the Cardiomyocyte Circadian Clock.

Ravi Sonkar,Martin E Young,Stuart J Frank,Mary N Latimer,Sumanth D Prabhu,Ryan Berry

doi:10.3389/fphar.2022.836725

Abstract

Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the hypothesis that the cardiomyopathy observed following cardiomyocyte circadian clock disruption may be secondary to chronic activation of cardiac GH/IGF1 signaling. Here, we report that cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit increased cardiac GH sensitivity, as evidenced by augmented GH-induced STAT5 phosphorylation (relative to littermate controls) in the heart (but not in the liver). Moreover, Igf1 mRNA levels are approximately 2-fold higher in CBK hearts (but not in livers), associated with markers of GH/IGF1 signaling activation (e.g., p-ERK, p-mTOR, and p-4EBP1) and adverse remodeling (e.g., cardiomyocyte hypertrophy and interstitial fibrosis). Genetic deletion of one allele of the GH receptor (GHR) normalized cardiac Igf1 levels in CBK hearts, associated with a partial normalization of adverse remodeling. This included attenuated progression of cardiomyopathy in CBK mice. Collectively, these observations suggest that excessive cardiac GH/IGF1 signaling contributes toward cardiomyopathy following genetic disruption of the cardiomyocyte circadian clock.

Highlights

All aspects of life fluctuate over the course of the day, often in parallel with environmental factors
The purpose of the present study was to investigate whether altered growth hormone (GH)/insulin-like growth factor 1 (IGF1) signaling in the heart contributes towards adverse cardiac remodeling following disruption of the cardiomyocyte circadian clock
Genetic disruption of the circadian clock mechanism results in adverse cardiac remodeling and dilated cardiomyopathy (Lefta et al, 2012; Kohsaka et al, 2014; Young et al, 2014; Ingle et al, 2015). This is exemplified by cardiomyocyte-specific BMAL1 knockout (CBK) mice, which have been reported to exhibit a hypertrophic phenotype by 12–16 weeks of age (Ingle et al, 2015)

Summary

Introduction

All aspects of life fluctuate over the course of the day, often in parallel with environmental factors (such as light intensity and ambient temperature). 24-h oscillations have been reported at cellular (e.g., transcription, translation, signaling), organ (e.g., muscle contractility, cognitive function), and whole body (e.g., sleep-wake and fasting-feeding behaviors) levels (Takahashi et al, 2008). Such 24h oscillations in biological processes are not solely the consequence of daily changes in environmental factors, as multiple rhythms persist during constant exogenous conditions (Takahashi et al, 2008). These intrinsic 24 h oscillations are termed circadian rhythms, and are driven by internal circadian clocks. The importance of circadian governance is underscored by reports that attenuation/ manipulation of circadian clocks through genetic (e.g., single nucleotide polymorphisms in humans or gene ablation in animal models) and/or environmental (e.g., shift work in humans or light/dark manipulation in animal models) means invariably increases pathology risk (e.g., obesity, diabetes mellitus, cardiovascular disease) (Knutsson et al, 1986; Turek et al, 2005; Davidson et al, 2006; Woon et al, 2007; Scott et al, 2008; Marcheva et al, 2010; Lefta et al, 2012; Knutsson and Kempe, 2014)

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