Functional role of sortilin in myogenesis and development of insulin-responsive glucose transport system in C2C12 myocytes.
Sortilin has been implicated in the formation of insulin-responsive GLUT4 storage vesicles in adipocytes by regulating sorting events between the trans-Golgi-network and endosomes. We herein show that sortilin serves as a potent myogenic differentiation stimulator for C2C12 myocytes by cooperatively functioning with p75NTR, which subsequently further contributes to development of the insulin-responsive glucose transport system in C2C12 myotubes. Sortilin expression was up-regulated upon C2C12 differentiation, and overexpression of sortilin in C2C12 cells significantly stimulated myogenic differentiation, a response that was completely abolished by either anti-p75NTR- or anti-nerve growth factor (NGF)-neutralizing antibodies. Importantly, small interference RNA-mediated suppression of endogenous sortilin significantly inhibited C2C12 differentiation, indicating the physiological significance of sortilin expression in the process of myogenesis. Although sortilin overexpression in C2C12 myotubes improved insulin-induced 2-deoxyglucose uptake, as previously reported, this effect apparently resulted from a decrease in the cellular content of GLUT1 and an increase in GLUT4 via differentiation-dependent alterations at both the gene transcriptional and the post-translational level. In addition, cellular contents of Ubc9 and SUMO-modified proteins appeared to be increased by sortilin overexpression. Taken together, these data demonstrate that sortilin is involved not only in development of the insulin-responsive glucose transport system in myocytes, but is also directly involved in muscle differentiation via modulation of proNGF-p75NTR.
Ariga
Miyako
M
21st Century COE program Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Nedachi
Taku
T
Katagiri
Hideki
H
Kanzaki
Makoto
M
D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003847:Deoxyglucose / Q000494:pharmacology; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism*; D024510:Muscle Development / Q000187:drug effects / Q000502:physiology*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D003847:Deoxyglucose; D005947:Glucose; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D008562:Membrane Glycoproteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D034741:RNA, Small Interfering; D017475:Receptors, Nerve Growth Factor; D025842:SUMO-1 Protein; D000099183:Sortilin; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; C517634:Ngfr protein, mouse; C489226:pro-nerve growth factor, mouse