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Insulin Stimulates Human Skeletal Muscle Protein Synthesis via an Indirect Mechanism Involving Endothelial-Dependent Vasodilation and Mammalian Target of Rapamycin Complex 1 Signaling

Timmerman, Kyle L., Lee, Jessica L., Dreyer, Hans C., Dhanani, Shaheen, Glynn, Erin L., Fry, Christopher S., Drummond, Micah J., Sheffield-Moore, Melinda, Rasmussen, Blake B., Volpi, Elena·2010·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2009-2696
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Abstract

Objective: Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism. Subjects: Subjects were healthy young adults (n = 14) aged 31 ± 2 yr. Design: Subjects were studied at baseline and during local leg infusion of insulin alone (control, n = 7) or insulin plus the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (l-NMMA, n = 7) to prevent insulin-induced vasodilation. Methods: We measured skeletal muscle protein metabolism with stable isotope tracers, blood flow with indocyanine green, capillary recruitment with contrast enhanced ultrasound, glucose metabolism with stable isotope tracers, and phosphorylation of proteins associated with insulin (Akt) and amino acid-induced mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling (mTOR, S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1) with Western blot analysis. Results: No basal differences between groups were detected. During insulin infusion, blood flow and capillary recruitment increased in the control (P < 0.05) group only; Akt phosphorylation and glucose uptake increased in both groups (P < 0.05), with no group differences; and mTORC1 signaling increased more in control (P < 0.05) than in l-NMMA. Phenylalanine net balance increased (P < 0.05) in both groups, but with opposite mechanisms: increased protein synthesis (basal, 0.051 ± 0.006 %/h; insulin, 0.077 ± 0.008 %/h; P < 0.05) with no change in proteolysis in control and decreased proteolysis (P < 0.05) with no change in synthesis (basal, 0.061 ± 0.004 %/h; insulin, 0.050 ± 0.006 %/h; P value not significant) in l-NMMA. Conclusions: Endothelial-dependent vasodilation and the consequent increase in nutritive flow and mTORC1 signaling, rather than Akt signaling, are fundamental mechanisms by which insulin stimulates muscle protein synthesis in humans. Additionally, these data underscore that insulin modulates skeletal muscle proteolysis according to its effects on nutritive flow.

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Research works printed but not linked: 49

  1. Kimball, 1996, Insulin and diabetes cause reciprocal changes in the association of eIF-4E and PHAS-I in rat skeletal muscle, Am J Physiol, 270, C705, 10.1152/ajpcell.1996.270.2.C705 · DOI
  2. Kimball, 1997, Insulin stimulates protein synthesis in skeletal muscle by enhancing the association of eIF-4E and eIF-4G, Am J Physiol, 272, C754, 10.1152/ajpcell.1997.272.2.C754 · DOI
  3. O'Connor, 2003, Insulin and amino acids independently stimulate skeletal muscle protein synthesis in neonatal pigs, Am J Physiol Endocrinol Metab, 284, E110, 10.1152/ajpendo.00326.2002 · DOI
  4. Suryawan, 2009, Differential regulation of protein synthesis by amino acids and insulin in peripheral and visceral tissues of neonatal pigs., Amino Acids, 37, 97, 10.1007/s00726-008-0149-z · DOI
  5. Bennet, 1991, Protein anabolic actions of insulin in the human body., Diabet Med, 8, 199, 10.1111/j.1464-5491.1991.tb01572.x · DOI
  6. Denne, 1991, Proteolysis in skeletal muscle and whole body in response to euglycemic hyperinsulinemia in normal adults, Am J Physiol, 261, E809
  7. Heslin, 1992, Effect of hyperinsulinemia on whole body and skeletal muscle leucine carbon kinetics in humans, Am J Physiol, 262, E911
  8. Moller-Loswick, 1994, Insulin selectively attenuates breakdown of nonmyofibrillar proteins in peripheral tissues of normal men, Am J Physiol, 266, E645
  9. Fujita, 2006, Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability, Am J Physiol Endocrinol Metab, 291, E745, 10.1152/ajpendo.00271.2005 · DOI · Paper page
  10. Fujita, 2009, Supraphysiological hyperinsulinaemia is necessary to stimulate skeletal muscle protein anabolism in older adults: evidence of a true age-related insulin resistance of muscle protein metabolism., Diabetologia, 52, 1889, 10.1007/s00125-009-1430-8 · DOI · Paper page
  11. Rasmussen, 2006, Insulin resistance of muscle protein metabolism in aging., FASEB J, 20, 768, 10.1096/fj.05-4607fje · DOI · Paper page
  12. Proud, 2002, Regulation of mammalian translation factors by nutrients., Eur J Biochem, 269, 5338, 10.1046/j.1432-1033.2002.03292.x · DOI · Paper page
  13. Baron, 2000, Interaction between insulin sensitivity and muscle perfusion on glucose uptake in human skeletal muscle: evidence for capillary recruitment., Diabetes, 49, 768, 10.2337/diabetes.49.5.768 · DOI
  14. Meneilly, 1995, Insulin-mediated increase in blood flow is impaired in the elderly., J Clin Endocrinol Metab, 80, 1899
  15. Tack, 1996, Direct vasodilator effects of physiological hyperinsulinaemia in human skeletal muscle., Eur J Clin Invest, 26, 772, 10.1046/j.1365-2362.1996.2020551.x · DOI
  16. Vincent, 2002, Skeletal muscle microvascular recruitment by physiological hyperinsulinemia precedes increases in total blood flow., Diabetes, 51, 42, 10.2337/diabetes.51.1.42 · DOI
  17. Hara, 1998, Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism., J Biol Chem, 273, 14484, 10.1074/jbc.273.23.14484 · DOI · Paper page
  18. Vincent, 2003, Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin, Am J Physiol Endocrinol Metab, 285, E123, 10.1152/ajpendo.00021.2003 · DOI · Paper page
  19. Nygren, 2003, Differential regulation of protein dynamics in splanchnic and skeletal muscle beds by insulin and amino acids in healthy human subjects., Diabetes, 52, 1377, 10.2337/diabetes.52.6.1377 · DOI
  20. Jorfeldt, 1971, Leg blood flow during exercise in man., Clin Sci, 41, 459, 10.1042/cs0410459 · DOI · Paper page
  21. Vincent, 2006, Mixed meal and light exercise each recruit muscle capillaries in healthy humans, Am J Physiol Endocrinol Metab, 290, E1191, 10.1152/ajpendo.00497.2005 · DOI
  22. Wei, 1998, Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion., Circulation, 97, 473, 10.1161/01.CIR.97.5.473 · DOI · Paper page
  23. Clerk, 2006, Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle., Diabetes, 55, 1436, 10.2337/db05-1373 · DOI · Paper page
  24. Wolfe, 1992, Radioactive and stable isotope tracers in biomedicine. In: Principles and practice of kinetic analysis
  25. Wolfe, 2005, Isotope tracers in metabolic research. In: Principles and practice of kinetic analysis
  26. Clerk, 2004, The vasodilatory actions of insulin on resistance and terminal arterioles and their impact on muscle glucose uptake., Diabetes Metab Res Rev, 20, 3, 10.1002/dmrr.414 · DOI
  27. Vincent, 2003, Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium., Curr Diab Rep, 3, 279, 10.1007/s11892-003-0018-9 · DOI
  28. Vincent, 2004, Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo., Diabetes, 53, 1418, 10.2337/diabetes.53.6.1418 · DOI · Paper page
  29. Kourembanas, 1993, Nitric oxide regulates the expression of vasoconstrictors and growth factors by vascular endothelium under both normoxia and hypoxia., J Clin Invest, 92, 99, 10.1172/JCI116604 · DOI · Paper page
  30. Mather, 2002, Endothelin contributes to basal vascular tone and endothelial dysfunction in human obesity and type 2 diabetes., Diabetes, 51, 3517, 10.2337/diabetes.51.12.3517 · DOI
  31. Wang, 2006, The vascular endothelial cell mediates insulin transport into skeletal muscle, Am J Physiol Endocrinol Metab, 291, E323, 10.1152/ajpendo.00047.2006 · DOI
  32. Wang, 2008, Insulin signaling stimulates insulin transport by bovine aortic endothelial cells., Diabetes, 57, 540, 10.2337/db07-0967 · DOI
  33. Roccio, 2006, Regulation of the small GTPase Rheb by amino acids., Oncogene, 25, 657, 10.1038/sj.onc.1209106 · DOI
  34. Long, 2005, Rheb binds and regulates the mTOR kinase., Curr Biol, 15, 702, 10.1016/j.cub.2005.02.053 · DOI · Paper page
  35. Long, 2005, Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency., J Biol Chem, 280, 23433, 10.1074/jbc.C500169200 · DOI · Paper page
  36. Manning, 2002, Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway., Mol Cell, 10, 151, 10.1016/S1097-2765(02)00568-3 · DOI · Paper page
  37. Alessi, 1996, Mechanism of activation of protein kinase B by insulin and IGF-1., EMBO J, 15, 6541, 10.1002/j.1460-2075.1996.tb01045.x · DOI · Paper page
  38. Vasudevan, 2009, AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer., Cancer Cell, 16, 21, 10.1016/j.ccr.2009.04.012 · DOI · Paper page
  39. Frost, 2009, Endotoxin and interferon-γ inhibit translation in skeletal muscle cells by stimulating nitric oxide synthase activity., Shock, 32, 416, 10.1097/SHK.0b013e3181a034d2 · DOI
  40. Percival, 2010, Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle., J Clin Invest, 120, 816, 10.1172/JCI40736 · DOI
  41. Casey, 2009, NOS inhibition blunts and delays the compensatory dilation in hypoperfused contracting human muscles., J Appl Physiol, 107, 1685, 10.1152/japplphysiol.00680.2009 · DOI
  42. Hillier, 1998, Extreme hyperinsulinemia unmasks insulin’s effect to stimulate protein synthesis in the human forearm, Am J Physiol, 274, E1067
  43. Newman, 1994, The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal muscle protein turnover in the human forearm., Metabolism, 43, 70, 10.1016/0026-0495(94)90159-7 · DOI
  44. Wolf, 1992, Growth hormone and insulin combine to improve whole-body and skeletal muscle protein kinetics, Surgery 112:284–291; discussion, 291
  45. Tessari, 1991, Effects of acute systemic hyperinsulinemia on forearm muscle proteolysis in healthy man., J Clin Invest, 88, 27, 10.1172/JCI115287 · DOI
  46. Bennet, 1990, Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia, Am J Physiol, 259, E185
  47. Gross, 2009, The role of FOXO in the regulation of metabolism., Curr Diab Rep, 9, 208, 10.1007/s11892-009-0034-5 · DOI
  48. Sandri, 2008, Signaling in muscle atrophy and hypertrophy., Physiology, 23, 160, 10.1152/physiol.00041.2007 · DOI · Paper page
  49. Guertin, 2006, Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1., Dev Cell, 11, 859, 10.1016/j.devcel.2006.10.007 · DOI · Paper page

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Metadata

Authors
Timmerman, K. L., Lee, J. L., Dreyer, H. C., Dhanani, S., Glynn, E. L., Fry, C. S., Drummond, M. J., Sheffield-Moore, M., Rasmussen, B. B., & Volpi, E.
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2010-08-01
Volume
95
Issue
8
Pages
3848-3857
ISSN
  • 0021-972X
  • 1945-7197
DOI
10.1210/jc.2009-2696
Cited by
154
References
4
Language
en

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