Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling

Kyle L. Timmerman, Jessica L. Lee, Hans C. Dreyer, Shaheen Dhanani, Erin L. Glynn, Christopher Fry, Micah J. Drummond, Melinda Sheffield-Moore, Blake Rasmussen, Elena Volpi

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3848-3857
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number8
DOIs
StatePublished - Aug 2010

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Muscle Proteins
Vasodilation
Skeletal Muscle
Insulin
omega-N-Methylarginine
Proteolysis
Phosphorylation
Metabolism
Isotopes
Blood
Eukaryotic Initiation Factor-4E
mechanistic target of rapamycin complex 1
Ribosomal Protein S6 Kinases
Glucose
Indocyanine Green
Sirolimus
Phenylalanine
Nitric Oxide Synthase
Muscle
Young Adult

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

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; Drummond, Micah J.; Sheffield-Moore, Melinda; Rasmussen, Blake; Volpi, Elena.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 8, 08.2010, p. 3848-3857.

Research output: Contribution to journalArticle

Timmerman, Kyle L. ; Lee, Jessica L. ; Dreyer, Hans C. ; Dhanani, Shaheen ; Glynn, Erin L. ; Fry, Christopher ; Drummond, Micah J. ; Sheffield-Moore, Melinda ; Rasmussen, Blake ; Volpi, Elena. / Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling. In: Journal of Clinical Endocrinology and Metabolism. 2010 ; Vol. 95, No. 8. pp. 3848-3857.
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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.",
author = "Timmerman, {Kyle L.} and Lee, {Jessica L.} and Dreyer, {Hans C.} and Shaheen Dhanani and Glynn, {Erin L.} and Christopher Fry and Drummond, {Micah J.} and Melinda Sheffield-Moore and Blake Rasmussen and Elena Volpi",
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T1 - Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling

AU - Timmerman, Kyle L.

AU - Lee, Jessica L.

AU - Dreyer, Hans C.

AU - Dhanani, Shaheen

AU - Glynn, Erin L.

AU - Fry, Christopher

AU - Drummond, Micah J.

AU - Sheffield-Moore, Melinda

AU - Rasmussen, Blake

AU - Volpi, Elena

PY - 2010/8

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N2 - 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.

AB - 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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