Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women

Experimental Gerontology

Volumn 65, Issue , 2015, Pages 1-7

  Markofski, Melissa M ^a,c   Dickinson, Jared M ^a,d   Drummond, Micah J ^a,e   Fry, Christopher S ^a   Fujita, Satoshi ^a,f   Gundermann, David M ^a   Glynn, Erin L ^a   Jennings, Kristofer ^a,b   Paddon Jones, Douglas ^a   Reidy, Paul T ^a   Sheffield Moore, Melinda ^a,b   Timmerman, Kyle L ^a,g   Rasmussen, Blake B ^a   Volpi, Elena ^a,b  

^a UNIVERSITY OF TEXAS MEDICAL BRANCH   (United States)

^b University of Texas Medical Branch School of Medicine   (United States)

^c UNIVERSITY OF HOUSTON   (United States)

^d ARIZONA STATE UNIVERSITY   (United States)

^e UNIVERSITY OF UTAH   (United States)

^f RITSUMEIKAN UNIVERSITY   (Japan)

^g MIAMI UNIVERSITY   (United States)

Author keywords

Aging; Gender; MTOR; Protein metabolism; Sarcopenia; Stable isotopes

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MUSCLE PROTEIN; S6 KINASE; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEX; RIBOSOMAL PROTEIN S6 KINASE, 70KD, POLYPEPTIDE 1; TARGET OF RAPAMYCIN KINASE;

ADULT; AGE; AGED; ARTICLE; BODY FAT; BODY MASS; COHORT ANALYSIS; DIET RESTRICTION; FAT FREE MASS; FEMALE; HUMAN; INSULIN RESISTANCE; MALE; NORMAL HUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS; SEX DIFFERENCE; SIGNAL TRANSDUCTION; WESTERN BLOTTING; AGING; BIOSYNTHESIS; COMPARATIVE STUDY; METABOLISM; MIDDLE AGED; MUSCLE CONTRACTION; PHOSPHORYLATION; PHYSIOLOGY; SKELETAL MUSCLE; VERY ELDERLY;

ADULT; AGE FACTORS; AGED; AGED, 80 AND OVER; AGING; FEMALE; HUMANS; MALE; MIDDLE AGED; MULTIPROTEIN COMPLEXES; MUSCLE CONTRACTION; MUSCLE PROTEINS; MUSCLE, SKELETAL; PHOSPHORYLATION; RIBOSOMAL PROTEIN S6 KINASES, 70-KDA; SEX FACTORS; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84924094844     PISSN: 05315565     EISSN: 18736815     Source Type: Journal    
DOI: 10.1016/j.exger.2015.02.015     Document Type: Article

References (69)

1. Balagopal P., Rooyackers O.E., Adey D.B., Ades P.A., Nair K.S. Effects of aging on in vivo synthesis of skeletal muscle myosin heavy-chain and sarcoplasmic protein in humans. Am. J. Physiol. 1997, 273:E790-E800.
2. Bhasin S., Woodhouse L., Storer T.W. Proof of the effect of testosterone on skeletal muscle. J. Endocrinol. 2001, 170:27-38.
3. Campbell W.W., Trappe T.A., Wolfe R.R., Evans W.J. The recommended dietary allowance for protein may not be adequate for older people to maintain skeletal muscle. J. Gerontol. A Biol. Sci. Med. Sci. 2001, 56:M373-M380.
4. Chalé-Rush A., Morris E.P., Kendall T.L., Brooks N.E., Fielding R.A. Effects of chronic overload on muscle hypertrophy and mTOR signaling in young adult and aged rats. J. Gerontol. A Biol. Sci. Med. Sci. 2009, 64:1232-1239.
5. Chevalier S., Goulet E.D., Burgos S.A., Wykes L.J., Morais J.A. Protein anabolic responses to a fed steady state in healthy aging. J. Gerontol. A Biol. Sci. Med. Sci. 2011, 66:681-688.
6. Cuthbertson D., Smith K., Babraj J., Leese G., Waddell T., Atherton P., et al. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J. 2005, 19:422-424.
7. Delmonico M.J., Harris T.B., Visser M., Park S.W., Conroy M.B., Velasquez-Mieyer P., et al. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am. J. Clin. Nutr. 2009, 90:1579-1585.
8. Dickinson J.M., Fry C.S., Drummond M.J., Gundermann D.M., Walker D.K., Glynn E.L., et al. Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids. J. Nutr. 2011, 141:856-862.
9. Dickinson J.M., Drummond M.J., Coben J.R., Volpi E., Rasmussen B.B. Aging differentially affects human skeletal muscle amino acid transporter expression when essential amino acids are ingested after exercise. Clin. Nutr. 2013, 32:273-280.
10. Dickinson J.M., Drummond M.J., Fry C.S., Gundermann D.M., Walker D.K., Timmerman K.L., et al. Rapamycin does not affect post-absorptive protein metabolism in human skeletal muscle. Metabolism 2013, 62:144-151.
11. Dreyer H.C., Fujita S., Glynn E.L., Drummond M.J., Volpi E., Rasmussen B.B. Resistance exercise increases leg muscle protein synthesis and mTOR signalling independent of sex. Acta Physiol. (Oxf.) 2010, 199:71-81.
12. Drummond M.J., Dreyer H.C., Pennings B., Fry C.S., Dhanani S., Dillon E.L., et al. Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging. J. Appl. Physiol. 2008, 104:1452-1461.
13. Drummond M.J., Fry C.S., Glynn E.L., Dreyer H.C., Dhanani S., Timmerman K.L., et al. Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. J. Physiol. 2009, 587:1535-1546.
14. Drummond M.J., Dickinson J.M., Fry C.S., Walker D.K., Gundermann D.M., Reidy P.T., et al. Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults. Am. J. Physiol. Endocrinol. Metab. 2012, 302:E1113-E1122.
15. Ferrando A.A., Lane H.W., Stuart C.A., Davis-Street J., Wolfe R.R. Prolonged bed rest decreases skeletal muscle and whole body protein synthesis. Am. J. Physiol. 1996, 270:E627-E633.
16. Fok W.C., Zhang Y., Salmon A.B., Bhattacharya A., Gunda R., Jones D., et al. Short-term treatment with rapamycin and dietary restriction have overlapping and distinctive effects in young mice. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68:108-116.
17. Fry C.S., Glynn E.L., Drummond M.J., Timmerman K.L., Fujita S., Abe T., et al. Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men. J. Appl. Physiol. 2010, 108:1199-1209.
18. Fry C.S., Drummond M.J., Glynn E.L., Dickinson J.M., Gundermann D.M., Timmerman K.L., et al. Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. Skelet. Muscle 2011, 1:11.
19. Fry C.S., Drummond M.J., Glynn E.L., Dickinson J.M., Gundermann D.M., Timmerman K.L., et al. Skeletal muscle autophagy and protein breakdown following resistance exercise are similar in younger and older adults. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68:599-607.
20. Fujita S., Rasmussen B.B., Cadenas J.G., Grady J.J., Volpi E. 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. 2006, 291:E745-E754.
21. Fujita S., Rasmussen B.B., Bell J.A., Cadenas J.G., Volpi E. Basal muscle intracellular amino acid kinetics in women and men. Am. J. Physiol. Endocrinol. Metab. 2007, 292:E77-E83.
22. Fujita S., Abe T., Drummond M.J., Cadenas J.G., Dreyer H.C., Sato Y., et al. Blood flow restriction during low-intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis. J. Appl. Physiol. 2007, 103:903-910.
23. Fujita S., Dreyer H.C., Drummond M.J., Glynn E.L., Volpi E., Rasmussen B.B. Essential amino acid and carbohydrate ingestion before resistance exercise does not enhance postexercise muscle protein synthesis. J. Appl. Physiol. 2009, 106:1730-1739.
24. Fujita S., Glynn E.L., Timmerman K.L., Rasmussen B.B., Volpi E. 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 2009, 52:1889-1898.
25. Fulgoni V.L. Current protein intake in America: analysis of the National Health and Nutrition Examination Survey, 2003-2004. Am. J. Clin. Nutr. 2008, 87:1554S-1557S.
26. Funai K., Parkington J.D., Carambula S., Fielding R.A. Age-associated decrease in contraction-induced activation of downstream targets of Akt/mTor signaling in skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006, 290:R1080-R1086.
27. Glynn E.L., Fry C.S., Drummond M.J., Timmerman K.L., Dhanani S., Volpi E., et al. Excess leucine intake enhances muscle anabolic signaling but not net protein anabolism in young men and women. J. Nutr. 2010, 140:1970-1976.
28. Glynn E.L., Fry C.S., Drummond M.J., Dreyer H.C., Dhanani S., Volpi E., et al. Muscle protein breakdown has a minor role in the protein anabolic response to essential amino acid and carbohydrate intake following resistance exercise. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2010, 299:R533-R540.
29. Glynn E.L., Fry C.S., Timmerman K.L., Drummond M.J., Volpi E., Rasmussen B.B. Addition of carbohydrate or alanine to an essential amino acid mixture does not enhance human skeletal muscle protein anabolism. J. Nutr. 2013, 143:307-314.
30. Guillet C., Prod'homme M., Balage M., Gachon P., Giraudet C., Morin L., et al. Impaired anabolic response of muscle protein synthesis is associated with S6K1 dysregulation in elderly humans. FASEB J. 2004, 18:1586-1587.
31. Guillet C., Delcourt I., Rance M., Giraudet C., Walrand S., Bedu M., et al. Changes in basal and insulin and amino acid response of whole body and skeletal muscle proteins in obese men. J. Clin. Endocrinol. Metab. 2009, 94:3044-3050.
32. Gundermann D.M., Fry C.S., Dickinson J.M., Walker D.K., Timmerman K.L., Drummond M.J., et al. Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise. J. Appl. Physiol. 2012, 112:1520-1528.
33. Hasten D.L., Pak-Loduca J., Obert K.A., Yarasheski K.E. Resistance exercise acutely increases MHC and mixed muscle protein synthesis rates in 78-84 and 23-32 yr olds. Am. J. Physiol. Endocrinol. Metab. 2000, 278:E620-E626.
34. Hauschke D., Steinijans V., Pigeot I. Bioequivalence Studies in Drug Development: Methods and Applications 2007, Wiley, Chichester, England; Hoboken, NJ.
35. Henderson G.C., Dhatariya K., Ford G.C., Klaus K.A., Basu R., Rizza R.A., et al. Higher muscle protein synthesis in women than men across the lifespan, and failure of androgen administration to amend age-related decrements. FASEB J. 2009, 23:631-641.
36. Jahn L., Barrett E., Genco M., Wei L., Spraggins T., Fryburg D. Tissue composition affects measures of postabsorptive human skeletal muscle metabolism: comparison across genders. J. Clin. Endocrinol. Metab. 1999, 84:1007-1010.
37. Kim P.L., Staron R.S., Phillips S.M. Fasted-state skeletal muscle protein synthesis after resistance exercise is altered with training. J. Physiol. 2005, 568:283-290.
38. Kumar V., Selby A., Rankin D., Patel R., Atherton P., Hildebrandt W., et al. Age-related differences in the dose-response relationship of muscle protein synthesis to resistance exercise in young and old men. J. Physiol. 2009, 587:211-217.
39. Lauretani F., Russo C.R., Bandinelli S., Bartali B., Cavazzini C., Di Iorio A., et al. Age-associated changes in skeletal muscles and their effect on mobility: an operational diagnosis of sarcopenia. J. Appl. Physiol. (1985) 2003, 95:1851-1860.
40. Li W., Miller R.A. Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. J. Gerontol. A Biol. Sci. Med. Sci. 2015, 70:263-272.
41. Li M., Verdijk L.B., Sakamoto K., Ely B., van Loon L.J., Musi N. Reduced AMPK-ACC and mTOR signaling in muscle from older men, and effect of resistance exercise. Mech. Ageing Dev. 2012, 133:655-664.
42. Miller B.F., Hansen M., Olesen J.L., Flyvbjerg A., Schwarz P., Babraj J.A., et al. No effect of menstrual cycle on myofibrillar and connective tissue protein synthesis in contracting skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2006, 290:E163-E168.
43. Miller B.F., Robinson M.M., Reuland D.J., Drake J.C., Peelor F.F., Bruss M.D., et al. Calorie restriction does not increase short-term or long-term protein synthesis. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68:530-538.
44. Morris B.J., Donlon T.A., He Q., Grove J.S., Masaki K.H., Elliott A., et al. Genetic analysis of TOR complex gene variation with human longevity: a nested case-control study of American men of Japanese ancestry. J. Gerontol. A Biol. Sci. Med. Sci. 2015, 70:133-142.
45. Parise G., Mihic S., MacLennan D., Yarasheski K.E., Tarnopolsky M.A. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J. Appl. Physiol. 2001, 91:1041-1047.
46. Parkington J.D., LeBrasseur N.K., Siebert A.P., Fielding R.A. Contraction-mediated mTOR, p70S6k, and ERK1/2 phosphorylation in aged skeletal muscle. J. Appl. Physiol. (1985) 2004, 97:243-248.
47. Reidy P.T., Walker D.K., Dickinson J.M., Gundermann D.M., Drummond M.J., Timmerman K.L., et al. Protein blend ingestion following resistance exercise promotes human muscle protein synthesis. J. Nutr. 2013, 143:410-416.
48. Smith G.I., Atherton P., Villareal D.T., Frimel T.N., Rankin D., Rennie M.J., et al. Differences in muscle protein synthesis and anabolic signaling in the postabsorptive state and in response to food in 65-80 year old men and women. PLoS One 2008, 3:e1875.
49. Smith P., Galea M., Woodward M., Said C., Dorevitch M. Physical activity by elderly patients undergoing inpatient rehabilitation is low: an observational study. Aust. J. Physiother. 2008, 54:209-213.
50. Smith G.I., Atherton P., Reeds D.N., Mohammed B.S., Jaffery H., Rankin D., et al. No major sex differences in muscle protein synthesis rates in the postabsorptive state and during hyperinsulinemia-hyperaminoacidemia in middle-aged adults. J. Appl. Physiol. 2009, 107:1308-1315.
51. Smith G.I., Villareal D.T., Sinacore D.R., Shah K., Mittendorfer B. Muscle protein synthesis response to exercise training in obese, older men and women. Med. Sci. Sports Exerc. 2012.
52. Smith G.I., Reeds D.N., Hall A.M., Chambers K.T., Finck B.N., Mittendorfer B. Sexually dimorphic effect of aging on skeletal muscle protein synthesis. Biol. Sex Differ. 2012, 3:11.
53. Timmerman K.L., Lee J.L., Dreyer H.C., Dhanani S., Glynn E.L., Fry C.S., et al. Insulin stimulates human skeletal muscle protein synthesis via an indirect mechanism involving endothelial-dependent vasodilation and mammalian target of rapamycin complex 1 signaling. J. Clin. Endocrinol. Metab. 2010, 95:3848-3857.
54. Timmerman K.L., Lee J.L., Fujita S., Dhanani S., Dreyer H.C., Fry C.S., et al. Pharmacological vasodilation improves insulin-stimulated muscle protein anabolism but not glucose utilization in older adults. Diabetes 2010, 59:2764-2771.
55. Timmerman K.L., Dhanani S., Glynn E.L., Fry C.S., Drummond M.J., Jennings K., et al. A moderate acute increase in physical activity enhances nutritive flow and the muscle protein anabolic response to mixed nutrient intake in older adults. Am. J. Clin. Nutr. 2012, 95:1403-1412.
56. Tremblay F., Krebs M., Dombrowski L., Brehm A., Bernroider E., Roth E., et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005, 54:2674-2684.
57. Villareal D.T., Smith G.I., Sinacore D.R., Shah K., Mittendorfer B. Regular multicomponent exercise increases physical fitness and muscle protein anabolism in frail, obese, older adults. Obesity (Silver Spring) 2011, 19:312-318.
58. Volpi E., Mittendorfer B., Rasmussen B.B., Wolfe R.R. The response of muscle protein anabolism to combined hyperaminoacidemia and glucose-induced hyperinsulinemia is impaired in the elderly. J. Clin. Endocrinol. Metab. 2000, 85:4481-4490.
59. Volpi E., Sheffield-Moore M., Rasmussen B.B., Wolfe R.R. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA 2001, 286:1206-1212.
60. Volpi E., Campbell W.W., Dwyer J.T., Johnson M.A., Jensen G.L., Morley J.E., et al. Is the optimal level of protein intake for older adults greater than the recommended dietary allowance?. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68:677-681.
61. Walker D.K., Dickinson J.M., Timmerman K.L., Drummond M.J., Reidy P.T., Fry C.S., et al. Exercise, amino acids, and aging in the control of human muscle protein synthesis. Med. Sci. Sports Exerc. 2011, 43:2249-2258.
62. Welle S. Human Protein Metabolism 1999, Springer, New York.
63. Welle S., Thornton C., Jozefowicz R., Statt M. Myofibrillar protein synthesis in young and old men. Am. J. Physiol. 1993, 264:E693-E698.
64. Welle S., Thornton C., Statt M. Myofibrillar protein synthesis in young and old human subjects after three months of resistance training. Am. J. Physiol. 1995, 268:E422-E427.
65. West D.W., Burd N.A., Churchward-Venne T.A., Camera D.M., Mitchell C.J., Baker S.K., et al. Sex-based comparisons of myofibrillar protein synthesis after resistance exercise in the fed state. J. Appl. Physiol. (1985) 2012, 112:1805-1813.
66. Yarasheski K.E., Zachwieja J.J., Bier D.M. Acute effects of resistance exercise on muscle protein synthesis rate in young and elderly men and women. Am. J. Physiol. 1993, 265:E210-E214.
67. Yarasheski K.E., Pak-Loduca J., Hasten D.L., Obert K.A., Brown M.B., Sinacore D.R. Resistance exercise training increases mixed muscle protein synthesis rate in frail women and men >/=76yr old. Am. J. Physiol. 1999, 277:E118-E125.
68. Yu Z., Wang R., Fok W.C., Coles A., Salmon A.B., Pérez V.I. Rapamycin and dietary restriction induce metabolically distinctive changes in mouse liver. J. Gerontol. A Biol. Sci. Med. Sci. 2014, Apri 22, [Epub ahead of print] PubMed PMID: 24755936.
69. Zhang Y., Bokov A., Gelfond J., Soto V., Ikeno Y., Hubbard G., et al. Rapamycin extends life and health in C57BL/6 mice. J. Gerontol. A Biol. Sci. Med. Sci. 2014, 69:119-130.