Neuregulin‐1β promotes myoblast differentiation and is anti‐cachexic in respiratory muscles of post‐infarcted swine

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 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 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 currently being 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. Skeletal muscle was collected at the time of euthanasia from the intercostal space and paired‐end RNA sequencing performed. NRG‐1β treatment altered expression of 583 transcripts including 242 transcripts altered at both doses. These included 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 skeletal muscle differentiation with an absolute requirement for ERBB signaling on myoblast 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.