Neuregulin-1beta modulates myogenesis in septic mouse serum-treated C2C12 myotubes in vitro through PPARgamma/NF-kappaB signaling

Sepsis-induced skeletal muscle atrophy is a pathological condition characterized by the loss of strength and muscle mass. Cytokine-induced apoptosis and impaired myogenesis play key roles in the development of this condition. However, the complete underlying mechanism remains largely unknown. Neuregulins are glial growth factors essential for myogenesis that regulate muscle metabolism. We investigated the role of neuregulin-1beta (NRG-1beta) in sepsis-induced apoptosis and myogenesis in skeletal muscle using a serum-based in vitro sepsis model. C2C12 myoblasts were differentiated by treatment with proliferative medium for 7 days. Then, cells were treated with 2% sham mouse serum, 1 nM NRG-1beta in 2% sham mouse serum, 2% septic mouse serum (SMS), or 1 nM NRG-1beta in 2% SMS. Exposure to SMS induced apoptosis, impaired myogenesis, and downregulated PPARgamma. NRG-1beta co-incubation remedied all these effects and inhibited NF-kappaB transcriptional activity. A specific PPARgamma antagonist (GW9662) was also administered as a 2-h pretreatment to block PPARgamma-mediated signaling and appeared to attenuate the effects of NRG-1beta. Taken together, our results demonstrate that NRG-1beta functions via a PPARgamma/NF-kappaB-dependent pathway to modulate myogenesis and protect against apoptosis in SMS-treated C2C12 myotubes.