Neuregulin (NRG-1β) Is Pro-Myogenic and Anti-Cachectic in Respiratory Muscles of Post-Myocardial Infarcted Swine

SIMPLE SUMMARY: Neuregulin is a growth factor that has been shown to prevent adverse remodeling in the heart and may represent a therapeutic for patients with systolic heart failure. A common symptom in heart failure is shortness of breath, which has been related in part to impaired skeletal muscle function. Since neuregulin directly activates skeletal muscle, in addition to heart tissue, we hypothesized that neuregulin might directly affect intercostal muscle gene expression changes in heart disease. We tested this hypothesis by performing global gene expression analysis of intercostal muscle tissue collected from pigs treated with recombinant neuregulin after the induction of myocardial infarction, an experimental model clinically similar to a human heart attack. We found that neuregulin-treated pigs had massive changes in global gene expression consistent with new muscle cell formation, as compared to untreated pigs. These data suggest that neuregulin is an important mediator of muscle function that can potentially be used to study heart disease-associated muscle dysfunction and the development of new therapeutics aimed at muscle repair in heart failure, as well as other diseases associated with muscle dysfunction and weakness. ABSTRACT: 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.