Abstract
Neuregulin-1, a growth factor that potentiates myogenesis induces glucose transport through translocation of glucose transporters, in an additive manner to insulin, in muscle cells. In this study, we examined the signaling pathway required for a recombinant active neuregulin-1 isoform (rhHeregulin-beta(1), 177-244, HRG) to stimulate glucose uptake in L6E9 myotubes. The stimulatory effect of HRG required binding to ErbB3 in L6E9 myotubes. PI3K activity is required for HRG action in both muscle cells and tissue. In L6E9 myotubes, HRG stimulated PKBalpha, PKBgamma, and PKCzeta activities. TPCK, an inhibitor of PDK1, abolished both HRG- and insulin-induced glucose transport. To assess whether PKB was necessary for the effects of HRG on glucose uptake, cells were infected with adenoviruses encoding dominant negative mutants of PKBalpha. Dominant negative PKB reduced PKB activity and insulin-stimulated glucose transport but not HRG-induced glucose transport. In contrast, transduction of L6E9 myotubes with adenoviruses encoding a dominant negative kinase-inactive PKCzeta abolished both HRG- and insulin-stimulated glucose uptake. In soleus muscle, HRG induced PKCzeta, but not PKB phosphorylation. HRG also stimulated the activity of p70S6K, p38MAPK, and p42/p44MAPK and inhibition of p42/p44MAPK partially repressed HRG action on glucose uptake. HRG did not affect AMPKalpha(1) or AMPKalpha(2) activities. In all, HRG stimulated glucose transport in muscle cells by activation of a pathway that requires PI3K, PDK1, and PKCzeta, but not PKB, and that shows cross-talk with the MAPK pathway. The PI3K, PDK1, and PKCzeta pathway can be considered as an alternative mechanism, independent of insulin, to induce glucose uptake.
Highlights
During adult life, NRGs are highly expressed in neurons and they act on the juxtaposed tissues contributing to the maintenance of differentiated patterns, such as the neuromuscular junction, NMJ (8 –12)
All three receptors are expressed in muscle tisp44MAPK and inhibition of p42/p44MAPK partially re- sue only ErbB2 and ErbB4 accumulate at the pressed HRG action on glucose uptake
Neuregulins-induced Glucose Transport Requires an Intact ErbB3 Binding Activity—In order to prove the necessity of the ErbB3 binding activity in the NRG action on glucose uptake in L6E9 myotubes, we used an antibody, Ab5, that binds to ErbB3 and blocks the NRG-binding domain
Summary
HRG stimulated glucose transport in muscle cells by activation of a pathway that requires PI3K, PDK1, and PKC, but not PKB, and that shows cross-talk with the MAPK pathway. A recent study indicates that muscle contraction, caused by either acute exercise or electrical stimulation, induces release of NRGs, to the extracellular milieu that results in ErbBsinduced-activity [40] Both exercise and oxidative stress induce glucose uptake through translocation of glucose transporters, in an additive and independent manner to the action of insulin, and AMPK has been suggested to be involved in this effect [41,42,43] controversy exists in this aspect. The additive effect of HRG and insulin on glucose uptake did not involve AMPK activation
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