Augmented cardiac growth hormone signaling in circadian-disrupted cardiomyopathy

Circadian disruption, including rotating shift work, social jet lag, and chronic sleep disturbance, is associated with increased cardiovascular risk and may promote cardiac remodeling. The molecular mechanisms connecting clock disruption to structural heart disease remain incompletely defined. This minireview advances the hypothesis that the growth hormone, GH, axis is an underrecognized endocrine mediator. GH secretion is time dependent, with most daily secretion occurring during early nocturnal sleep-in humans. Cardiomyocytes express GH receptors, and GH can activate Janus kinase 2, signal transducer and activator of transcription 5, phosphoinositide 3 kinase and Akt, and mitogen activated protein kinase and extracellular signal regulated kinase pathways that influence cardiac growth and metabolism. We propose that the cardiomyocyte molecular clock restricts GH responsiveness to circadian phases. REV ERBα is a plausible component of this restraint, but direct cardiomyocyte evidence is lacking. Circadian disruption may increase or mistime myocardial GH signaling, promoting hypertrophy, fibrosis, and metabolic inflexibility. The strongest support comes from cardiomyocyte specific Bmal1 deficient mice, which show increased GH induced cardiac STAT5 phosphorylation, increased cardiac Igf1 expression, and remodeling. Reduction of GH receptor gene dosage partially attenuates this phenotype, supporting a causal contribution of cardiac GH signaling. Nevertheless, genetic clock ablation is not equivalent to environmental circadian misalignment in shift work or chronic sleep disruption. We critically evaluate the components of this proposed clock-GH-heart axis, identify unresolved questions, and outline experiments and chronopharmacological strategies to test whether restoring temporal control of GH signaling can prevent pathological remodeling while preserving physiological GH action.