Neuregulins mediate calcium-induced glucose transport during muscle contraction.
Neuregulin, a growth factor involved in myogenesis, has rapid effects on muscle metabolism. In a manner analogous to insulin and exercise, neuregulins stimulate glucose transport through recruitment of glucose transporters to surface membranes in skeletal muscle. Like muscle contraction, neuregulins have additive effects with insulin on glucose uptake. Therefore, we examined whether neuregulins are involved in the mechanism by which muscle contraction regulates glucose transport. We show that caffeine-induced increases in cytosolic Ca2+ mediate a metalloproteinase-dependent release of neuregulins, which stimulates tyrosine phosphorylation of ErbB4 receptors. Activation of ErbB4 is necessary for Ca2+-derived effects on glucose transport. Furthermore, blockage of ErbB4 abruptly impairs contraction-induced glucose uptake in slow twitch muscle fibers, and to a lesser extent, in fast twitch muscle fibers. In conclusion, we provide evidence that contraction-induced activation of neuregulin receptors is necessary for the stimulation of glucose transport and a key element of energetic metabolism during muscle contraction.
Cantó
Carles
C
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and Institut de Recerca Biomèdica, Parc Científic de Barcelona, E-08028 Barcelona, Spain.
Chibalin
Alexander V
AV
Karolinska Institutet, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, SE-171 77 Stockholm, Sweden.
Barnes
Brian R
BR
Karolinska Institutet, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, SE-171 77 Stockholm, Sweden.
Glund
Stephan
S
Karolinska Institutet, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, SE-171 77 Stockholm, Sweden.
Suárez
Elisabet
E
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and Institut de Recerca Biomèdica, Parc Científic de Barcelona, E-08028 Barcelona, Spain.
Ryder
Jeffrey W
JW
Karolinska Institutet, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, SE-171 77 Stockholm, Sweden.
Palacín
Manuel
M
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and Institut de Recerca Biomèdica, Parc Científic de Barcelona, E-08028 Barcelona, Spain.
Zierath
Juleen R
JR
Karolinska Institutet, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, SE-171 77 Stockholm, Sweden.
Zorzano
Antonio
A
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and Institut de Recerca Biomèdica, Parc Científic de Barcelona, E-08028 Barcelona, Spain.
Gumà
Anna
A
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and Institut de Recerca Biomèdica, Parc Científic de Barcelona, E-08028 Barcelona, Spain. Electronic address: aguma@ub.edu.
D000818:Animals; D001692:Biological Transport; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D020880:Neuregulins / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D066247:Receptor, ErbB-4; D014443:Tyrosine / Q000378:metabolism
D020880:Neuregulins; D002110:Caffeine; D014443:Tyrosine; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D005947:Glucose; D002118:Calcium