The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTor signaling in vivo and the expression of myogenic genes in vitro

Amy Dukes, Colleen M. Davis, Mona El Refaey, Sunil Upadhyay, Sarah Mork, Phonepasong Arounleut, Maribeth H Johnson, William D Hill, Carlos M Isales, Mark W Hamrick

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Objectives: Nutrition plays a key role in the maintenance of muscle and bone mass, and dietary protein deficiency has in particular been associated with catabolism of both muscle and bone tissue. One mechanism thought to link protein deficiency with loss of muscle mass is deficiency in specific amino acids that play a role in muscle metabolism. The aim of this study was to test the hypothesis that the essential amino acid tryptophan, and its metabolite kynurenine, might directly affect muscle metabolism in the setting of protein deficiency. Methods: Adult mice (12 mo) were fed a normal diet (18% protein), as well as diets with low protein (8%) supplemented with increasing concentrations (50, 100, and 200 uM) of kynurenine (Kyn) or with tryptophan (Trp; 1.5 mM) for 8 weeks. Myoprogenitor cells were also treated with Trp and Kyn in vitro to determine their effects on cell proliferation and expression of myogenic differentiation markers. Results: All mice on the low-protein diets weighed less than the group fed normal protein (18%). Lean mass measured by dual-energy X-ray absorptiometry was lowest in mice on the high Kyn diet, whereas percent lean mass was highest in mice receiving Trp supplementation and percent body fat was lowest in mice receiving Trp. Enzyme-linked immunosorbent assays showed significant increases in skeletal muscle insulin-like growth factor-1, leptin, and the myostatin antagonist follistatin with Trp supplementation. mRNA microarray and gene pathway analysis performed on muscle samples demonstrate that mTor/eif4/p70s6k pathway molecules are significantly up-regulated in muscles from mice on Kyn and Trp supplementation. In vitro, neither amino acid affected proliferation of myoprogenitors, but Trp increased the expression of the myogenic markers MyoD, myogenin, and myosin heavy chain. Conclusion: These findings suggest that dietary amino acids can directly affect molecular signaling in skeletal muscle, further indicating that dietary manipulation with specific amino acids could potentially attenuate muscle loss with dietary protein deficiency.

Original languageEnglish (US)
Pages (from-to)1018-1024
Number of pages7
JournalNutrition
Volume31
Issue number7-8
DOIs
StatePublished - Jan 1 2015

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70-kDa Ribosomal Protein S6 Kinases
Aromatic Amino Acids
Tryptophan
Kynurenine
Skeletal Muscle
Gene Expression
Protein Deficiency
Muscles
Amino Acids
Protein-Restricted Diet
Dietary Proteins
Myostatin
Follistatin
Myogenin
Diet
Bone and Bones
Essential Amino Acids
Myosin Heavy Chains
In Vitro Techniques
Differentiation Antigens

Keywords

  • Aging
  • C2 C12 cells
  • Muscle atrophy
  • Pathway analysis
  • Sarcopenia

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

Cite this

The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTor signaling in vivo and the expression of myogenic genes in vitro. / Dukes, Amy; Davis, Colleen M.; El Refaey, Mona; Upadhyay, Sunil; Mork, Sarah; Arounleut, Phonepasong; Johnson, Maribeth H; Hill, William D; Isales, Carlos M; Hamrick, Mark W.

In: Nutrition, Vol. 31, No. 7-8, 01.01.2015, p. 1018-1024.

Research output: Contribution to journalArticle

Dukes, Amy ; Davis, Colleen M. ; El Refaey, Mona ; Upadhyay, Sunil ; Mork, Sarah ; Arounleut, Phonepasong ; Johnson, Maribeth H ; Hill, William D ; Isales, Carlos M ; Hamrick, Mark W. / The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTor signaling in vivo and the expression of myogenic genes in vitro. In: Nutrition. 2015 ; Vol. 31, No. 7-8. pp. 1018-1024.
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AU - Dukes, Amy

AU - Davis, Colleen M.

AU - El Refaey, Mona

AU - Upadhyay, Sunil

AU - Mork, Sarah

AU - Arounleut, Phonepasong

AU - Johnson, Maribeth H

AU - Hill, William D

AU - Isales, Carlos M

AU - Hamrick, Mark W

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N2 - Objectives: Nutrition plays a key role in the maintenance of muscle and bone mass, and dietary protein deficiency has in particular been associated with catabolism of both muscle and bone tissue. One mechanism thought to link protein deficiency with loss of muscle mass is deficiency in specific amino acids that play a role in muscle metabolism. The aim of this study was to test the hypothesis that the essential amino acid tryptophan, and its metabolite kynurenine, might directly affect muscle metabolism in the setting of protein deficiency. Methods: Adult mice (12 mo) were fed a normal diet (18% protein), as well as diets with low protein (8%) supplemented with increasing concentrations (50, 100, and 200 uM) of kynurenine (Kyn) or with tryptophan (Trp; 1.5 mM) for 8 weeks. Myoprogenitor cells were also treated with Trp and Kyn in vitro to determine their effects on cell proliferation and expression of myogenic differentiation markers. Results: All mice on the low-protein diets weighed less than the group fed normal protein (18%). Lean mass measured by dual-energy X-ray absorptiometry was lowest in mice on the high Kyn diet, whereas percent lean mass was highest in mice receiving Trp supplementation and percent body fat was lowest in mice receiving Trp. Enzyme-linked immunosorbent assays showed significant increases in skeletal muscle insulin-like growth factor-1, leptin, and the myostatin antagonist follistatin with Trp supplementation. mRNA microarray and gene pathway analysis performed on muscle samples demonstrate that mTor/eif4/p70s6k pathway molecules are significantly up-regulated in muscles from mice on Kyn and Trp supplementation. In vitro, neither amino acid affected proliferation of myoprogenitors, but Trp increased the expression of the myogenic markers MyoD, myogenin, and myosin heavy chain. Conclusion: These findings suggest that dietary amino acids can directly affect molecular signaling in skeletal muscle, further indicating that dietary manipulation with specific amino acids could potentially attenuate muscle loss with dietary protein deficiency.

AB - Objectives: Nutrition plays a key role in the maintenance of muscle and bone mass, and dietary protein deficiency has in particular been associated with catabolism of both muscle and bone tissue. One mechanism thought to link protein deficiency with loss of muscle mass is deficiency in specific amino acids that play a role in muscle metabolism. The aim of this study was to test the hypothesis that the essential amino acid tryptophan, and its metabolite kynurenine, might directly affect muscle metabolism in the setting of protein deficiency. Methods: Adult mice (12 mo) were fed a normal diet (18% protein), as well as diets with low protein (8%) supplemented with increasing concentrations (50, 100, and 200 uM) of kynurenine (Kyn) or with tryptophan (Trp; 1.5 mM) for 8 weeks. Myoprogenitor cells were also treated with Trp and Kyn in vitro to determine their effects on cell proliferation and expression of myogenic differentiation markers. Results: All mice on the low-protein diets weighed less than the group fed normal protein (18%). Lean mass measured by dual-energy X-ray absorptiometry was lowest in mice on the high Kyn diet, whereas percent lean mass was highest in mice receiving Trp supplementation and percent body fat was lowest in mice receiving Trp. Enzyme-linked immunosorbent assays showed significant increases in skeletal muscle insulin-like growth factor-1, leptin, and the myostatin antagonist follistatin with Trp supplementation. mRNA microarray and gene pathway analysis performed on muscle samples demonstrate that mTor/eif4/p70s6k pathway molecules are significantly up-regulated in muscles from mice on Kyn and Trp supplementation. In vitro, neither amino acid affected proliferation of myoprogenitors, but Trp increased the expression of the myogenic markers MyoD, myogenin, and myosin heavy chain. Conclusion: These findings suggest that dietary amino acids can directly affect molecular signaling in skeletal muscle, further indicating that dietary manipulation with specific amino acids could potentially attenuate muscle loss with dietary protein deficiency.

KW - Aging

KW - C2 C12 cells

KW - Muscle atrophy

KW - Pathway analysis

KW - Sarcopenia

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