Neuregulin-1β (NRG-1β) is a growth and differentiation factor with pleiotropic systemic effects. Because NRG-1β has therapeutic potential for heart failure and has known growth effects in skeletal muscle, we hypothesized that it might affect heart failure-associated cachexia, a severe co-morbidity characterized by a loss of muscle mass. We therefore assessed NRG-1β’s effect on intercostal skeletal muscle gene expression in a swine model of heart failure using recombinant glial growth factor 2 (USAN-cimaglermin alfa), a version of NRG-1β that has been tested in humans with systolic heart failure. Animals received one of two intravenous doses (0.67 or 2 mg/kg) of NRG-1β bi-weekly for 4 weeks, beginning one week after infarct. Based on paired-end RNA sequencing, NRG-1β treatment altered the intercostal muscle gene expression of 581 transcripts, including genes required for myofiber growth, maintenance and survival, such as MYH3, MYHC, MYL6B, KY and HES1. Importantly, NRG-1β altered the directionality of at least 85 genes associated with cachexia, including myostatin, which negatively regulates myoblast differentiation by down-regulating MyoD expression. Consistent with this, MyoD was increased in NRG-1β-treated animals. In vitro experiments with myoblast cell lines confirmed that NRG-1β induces ERBB-dependent differentiation. These findings suggest a NRG-1β-mediated anti-atrophic, anti-cachexia effect that may provide additional benefits to this potential therapy in heart failure.

Within the injured heart, cells are exposed to elevated retinoic acid signaling resulting from mobilized stores of its precursor, vitamin A, and increased cardiac expression of synthesizing enzymes. This study investigated the effects of retinoic acid, a potent regulator of cell fate and function, on human proliferative cardiac cell clones derived from left ventricle biopsies. The results show an increase in inflammatory factor secretion, immune cell activation, and decreased extracellular matrix expression.

Hepatic stores of Vitamin A (retinol) are mobilized and metabolized in the heart following myocardial infarction. The physiological consequences of this mobilization are poorly understood. Here we used dietary depletion in a lecithin retinol acyltransferase mutant mouse line to induce Vitamin A deficiency and investigate the effects on cardiac function and recovery from myocardial infarction. We found that uninjured Vitamin A-depleted hearts had decreased contractile function but, paradoxically, improved recovery after injury. These effects on cardiac function were specific to male mice, which experienced more rapid and severe depletion of circulating Vitamin A. Following injury, Vitamin A deficiency also caused hepatic hypolipidemia and gene expression changes in heart and liver suggesting altered metabolism contributed to cardiac phenotypes.

Cardiac signaling proteins sensitive to changes in cardiac status may help predict the cardiac effects of doxorubicin in children with acute lymphoblastic