Neuregulins Increase Mitochondrial Oxidative Capacity and Insulin Sensitivity in Skeletal Muscle Cells

Abstract

OBJECTIVE-Neuregulins are growth factors that are essential for myogenesis and regulate muscle metabolism. The addition of a recombinant neuregulin-1 isoform, heregulin-␤1 177-244 (Hrg), containing 3 nmol/l of the bioactive epidermal growth factor-like domain, to developing L6E9 myocytes has acute and chronic effects on glucose uptake and enhances myogenesis. Here, we studied the metabolic adaptation of myocytes to chronic treatments with Hrg. RESEARCH DESIGN AND METHODS-L6E9and C2C12 myocytes were chronically treated with low concentrations of Hrg (3 pmol/l) that do not induce myogenesis. We analyzed the effects of Hrg on cellular oxidative metabolism and insulin sensitivity and explored the mechanisms of action.RESULTS-Hrg increased the cell content of GLUT4 without affecting basal glucose uptake. Glucose and palmitate oxidation increased in Hrg-treated cells, whereas lactate release decreased. Hrg increased the abundance of oxidative phosphorylation (OX-PHOS) subunits, enhanced mitochondrial membrane potential, and induced the expression of peroxisome proliferator-activated receptor (PPAR)␥ coactivator1␣ and PPAR␦. Furthermore, we identified PPAR␦ as an essential mediator of the stimulatory effects of Hrg on the expression of OXPHOS subunits. The higher oxidative capacity of L6E9 myotubes after neuregulin treatment also paralleled an increase in insulin sensitivity and insulin signaling potency.CONCLUSIONS-These results indicate that neuregulins act as key modulators of oxidative capacity and insulin sensitivity in muscle cells.

Extracellular growth factors and mitogens cooperate to drive mitochondrial biogenesis

“…PRC is the only family member induced at the RNA level following NRG plus IGF treatment but siRNA analysis indicated that this induction is not required. Schwann cells express both PGC-1- and PGC-1- and it is possible that either or both of these are involved, especially as the PGC-1 family are subject to multiple post-translational modifications and have been reported to be regulated by NRG (Canto et al, 2007;Lin et al, 2005). Alternatively, other transcriptional coactivators might be involved.…”

“…Alternatively, other transcriptional coactivators might be involved. Other transcription factors might also be important: for example ERR has been shown to cooperate with NRF1 and NRF2 (Schreiber et al, 2004) and NRG has been shown to phosphorylate and induce NRF2-mediated mitochondrial gene expression (Canto et al, 2007;Fromm and Burden, 2001). Further studies will be required to dissect what is likely to be a highly regulated process.…”

Emerging role of neuregulin as a modulator of muscle metabolism

“…In L6E9 muscle cells, NRG increases the expression of PGC-1␣ and PPAR␦, whereas PPAR␣ and -␥ are undetectable in these cultured cells despite the fact that skeletal muscle tissue expresses relatively high levels of PPAR␣. The NRG-dependent increase in mitochondrial activity is abrogated in a PPAR␦-dominant negative model but unaltered by PPAR␥ inhibition (9). PPAR␦ participates in muscle adaptation to training by increasing endurance capacity as a result of its effects on oxidative capacity, respiratory complex content, and PGC-1␣ expression (68,76).…”

“…Moreover, NRG increases the expression of multiple components of the insulin-signaling cascade in a PPAR␦-dependent manner (Fig. 3) (9). Given the similarities between the insulin and IGF-I signaling pathways, it would also be relevant to study whether NRG potentiates the IGF-I cascade.…”

Glial Growth Factor 2 protects doxorubicin exposed cardiomyocytes through BAD/Bcl-2 pathway activation

“…Studies in quiescent adult rat ventricular cardiomyocytes show that NRG1 influences gene expression of multiple cellular systems, including factors involved in mitochondrial metabolism [9]. Additionally, in skeletal muscle, NRG1 treatment increased mitochondrial activity and membrane potential [37]. When assessing gene, expression using a panel focused on mitochondrial function we found that GGF2, when present by itself, did not dramatically alter expression of the studied mitochondrial related genes as seen in Figure 6.…”