A Novel Role of Neuregulin in Skeletal Muscle

Abstract

Neuregulins regulate the expression of acetylcholine receptor genes and induce development of the neuromuscular junction in muscle. In studying whether neuregulins regulate glucose uptake in muscle, we analyzed the effect of a recombinant neuregulin, r heregulin-␤1-(177-244) (HRG), on L6E9 muscle cells, which express the neuregulin receptors ErbB2 and ErbB3. L6E9 responded acutely to HRG by a time-and concentrationdependent stimulation of 2-deoxyglucose uptake. HRGinduced stimulation of glucose transport was additive to the effect of insulin. The acute stimulation of the glucose transport induced by HRG was a consequence of the translocation of GLUT4, GLUT1, and GLUT3 glucose carriers to the cell surface. The effect of HRG on glucose transport was dependent on phosphatidylinositol 3-kinase activity. HRG also stimulated glucose transport in the incubated soleus muscle and was additive to the effect of insulin. Chronic exposure of L6E9 cells to HRG potentiated myogenic differentiation, and under these conditions, glucose transport was also stimulated. The activation of glucose transport after chronic HRG exposure was due to enhanced cell content of GLUT1 and GLUT3 and to increased abundance of these carriers at the plasma membrane. However, under these conditions, GLUT4 expression was markedly down-regulated. Muscle denervation is associated with GLUT1 induction and GLUT4 repression. In this connection, muscle denervation caused a marked increase in the content of ErbB2 and ErbB3 receptors, which occurred in the absence of alterations in neuregulin mRNA levels. This fact suggests that neuregulins regulate glucose transporter expression in denervated muscle. We conclude that neuregulins regulate glucose uptake in L6E9 muscle cells by mechanisms involving the recruitment of glucose transporters to the cell surface and modulation of their expression. Neuregulins may also participate in the adaptations in glucose transport that take place in the muscle fiber after denervation.

Neuregulins Mediate Calcium-induced Glucose Transport during Muscle Contraction

“…Our observation showing that neuregulins mediate contraction-induced glucose uptake clarify previous data reporting the additive effects of neuregulins and insulin on glucose uptake in skeletal muscle and L6E9 myotubes (17). However, the effect of neuregulins on PI3K (15,17) remains controversial.…”

“…However, the effect of neuregulins on PI3K (15,17) remains controversial. Although ex vivo contraction-induced glucose uptake seems to be mediated by a PI3K-independent pathway (30,31), there is evidence that wortmannin, a PI3K-specific inhibitor, partially inhibits contraction-induced glucose uptake in perfused rat hindlimb (32,33).…”

“…Total Muscle Lysates, Immunoprecipitation, and Western Blot-All these procedures were performed essentially as described previously (15,17). For total lysates, a frozen muscle strip was collected in an Eppendorf tube placed on ice and pulverized with an Eppendorf homogenizer.…”

Neuregulin induces the expression of transcription factors and myosin heavy chains typical of muscle spindles in cultured human muscle

“…In skeletal myotubes maintained in vitro, NRG regulates the number of acetylcholine receptors (AChRs) (16,17), the subunit compositions of AChRs (18), and the expression of other critical proteins (11,19,20). These findings suggest that NRG acts at the neuromuscular junction (NMJ) to help maintain the AChR density essential for effective transmission at this synapse.…”

“…In the motor neuron-muscle system, NRG has been implicated in the maturation of the postsynaptic membrane at the neuromuscular junction (6)(7)(8), the survival of Schwann cell precursors (9), the maturation of Schwann cells in peripheral nerve (10), glucose metabolism (11), and myogenesis (12). The NRG͞ErbB system has also been implicated in muscle spindle formation (13)(14)(15).…”