Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis

Springer Science and Business Media LLC - Tập 1 Số 1 - 2011
Christopher S. Fry1, Micah J. Drummond, Erin L. Glynn, Jared M. Dickinson, David M. Gundermann, Kyle L. Timmerman, D.M.H. Walker, Shaheen Dhanani, Elena Volpi, Blake B. Rasmussen
1Division of Rehabilitation Sciences, University of Texas Medical Branch, Galveston, Texas, 77550 USA. [email protected]

Tóm tắt

Abstract Background Sarcopenia, the loss of skeletal muscle mass during aging, increases the risk for falls and dependency. Resistance exercise (RE) training is an effective treatment to improve muscle mass and strength in older adults, but aging is associated with a smaller amount of training-induced hypertrophy. This may be due in part to an inability to stimulate muscle-protein synthesis (MPS) after an acute bout of RE. We hypothesized that older adults would have impaired mammalian target of rapamycin complex (mTORC)1 signaling and MPS response compared with young adults after acute RE. Methods We measured intracellular signaling and MPS in 16 older (mean 70 ± 2 years) and 16 younger (27 ± 2 years) subjects. Muscle biopsies were sampled at baseline and at 3, 6 and 24 hr after exercise. Phosphorylation of regulatory signaling proteins and MPS were determined on successive muscle biopsies by immunoblotting and stable isotopic tracer techniques, respectively. Results Increased phosphorylation was seen only in the younger group (P< 0.05) for several key signaling proteins after exercise, including mammalian target of rapamycin (mTOR), ribosomal S6 kinase (S6K)1, eukaryotic initiation factor 4E-binding protein (4E-BP)1 and extracellular signal-regulated kinase (ERK)1/2, with no changes seen in the older group (P > 0.05). After exercise, MPS increased from baseline only in the younger group (P< 0.05), with MPS being significantly greater than that in the older group (P < 0.05). Conclusions We conclude that aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. These age-related differences may contribute to the blunted hypertrophic response seen after resistance-exercise training in older adults, and highlight the mTORC1 pathway as a key therapeutic target to prevent sarcopenia.

Từ khóa


Tài liệu tham khảo

Bassey EJ, Fiatarone MA, Oneill EF, Kelly M, Evans WJ, Lipsitz LA: Leg extensor power and functional performance in very old men and women. Clin Sci 1992, 82: 321-327.

Bortz WM: Disuse and aging. JAMA 1982, 248: 1203-1208. 10.1001/jama.248.10.1203

Baumgartner RN, Stauber PM, McHugh D, Koehler KM, Garry PJ: Cross sectional age-differences in body composition in persons 60+ years of age. J Gerontol A Biol Sci Med Sci 1995, 50: M307-M316.

Volpi E, Mittendorfer B, Rasmussen BB, Wolfe RR: 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. 10.1210/jc.85.12.4481

Volpi E, Sheffield-Moore M, Rasmussen BB, Wolfe RR: Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA 2001, 286: 1206-1212. 10.1001/jama.286.10.1206

Cuthbertson D, Smith K, Babraj J, Leese G, Waddell T, Atherton P, Wackerhage H, Taylor PM, Rennie MJ: Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J 2005, 19: 422-424.

Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR: Aging is associated with diminished accretion of muscle proteins after the ingestion of a small bolus of essential amino acids. Am J Clin Nutr 2005, 82: 1065-1073.

Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR: A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 2006, 291: E381-387. 10.1152/ajpendo.00488.2005

Rasmussen BB, Fujita S, Wolfe RR, Mittendorfer B, Roy M, Rowe VL, Volpi E: Insulin resistance of muscle protein metabolism in aging. FASEB J 2006, 20: 768-769.

Volpi E, Mittendorfer B, Wolfe RR: Insulin resistance in the elderly. Diabetes 1998, 47: A426-A426.

Volpi E, Mittendorfer B, Wolfe RR: Muscle protein anabolism during meal absorption is impaired in the elderly due to insulin resistance at the protein metabolism level. Diabetologia 1998, 41: A204-A204.

Volpi E, Mittendorfer B, Rasmussen BB, Wolfe RR: Muscle protein synthesis is impaired in the elderly during physiologic hyperinsulinemia. Diabetes 2001, 50: A300-A301.

Kumar V, Selby A, Rankin D, Patel R, Atherton P, Hildebrandt W, Williams J, Smith K, Seynnes O, Hiscock N, Rennie MJ: 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. 10.1113/jphysiol.2008.164483

Mayhew DL, Kim JS, Cross JM, Ferrando AA, Bamman MM: Translational signaling responses preceding resistance training-mediated myofiber hypertrophy in young and old humans. J Appl Physiol 2009, 107: 1655-1662. 10.1152/japplphysiol.91234.2008

Dreyer HC, Fujita S, Cadenas JG, Chinkes DL, Volpi E, Rasmussen BB: Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol 2006, 576: 613-624. 10.1113/jphysiol.2006.113175

Phillips SM, Tipton KD, Aarsland A, Wolf SE, Wolfe RR: Mixed muscle protein synthesis and breakdown after resistance exercise in humans. Am J Physiol Endocrinol Metab 1997, 36: E99-E107.

Phillips SM, Tipton KD, Ferrando AA, Wolfe RR: Resistance training reduces the acute exercise-induced increase in muscle protein turnover. Am J Physiol Endocrinol Metab 1999, 276: E118-E124.

Biolo G, Maggi SP, Williams BD, Tipton KD, Wolfe RR: Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans. Am J Physiol 1995, 268: E514-520.

Kosek DJ, Kim JS, Petrella JK, Cross JM, Bamman MM: Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults. J Appl Physiol 2006, 101: 531-544. 10.1152/japplphysiol.01474.2005

Petrella JK, Kim JS, Cross JM, Kosek DJ, Bamman MM: Efficacy of myonuclear addition may explain differential myofiber growth among resistance-trained young and older men and women. Am J Physiol Endocrinol Metab 2006, 291: E937-E946. 10.1152/ajpendo.00190.2006

Kosek DJ, Bamman MM: Modulation of the dystrophin-associated protein complex in response to resistance training in young and older men. J Appl Physiol 2008, 104: 1476-1484. 10.1152/japplphysiol.00708.2007

Nader GA: Molecular determinants of skeletal muscle mass: getting the "AKT" together. Int J Biochem Cell Biol 2005, 37: 1985-1996. 10.1016/j.biocel.2005.02.026

Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW: Control of the size of the human muscle mass. Annu Rev Physiol 2004, 66: 799-828. 10.1146/annurev.physiol.66.052102.134444

Kimball SR, Farrell PA, Jefferson LS: Invited review: role of insulin in translational control of protein synthesis in skeletal muscle by amino acids or exercise. J Appl Physiol 2002, 93: 1168-1180.

Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD: Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001, 3: 1014-1019. 10.1038/ncb1101-1014

Baar K, Esser K: Phosphorylation of p70(S6 k) correlates with increased skeletal muscle mass following resistance exercise. Am J Physiol 1999, 276: C120-127.

Terzis G, Georgiadis G, Stratakos G, Vogiatzis I, Kavouras S, Manta P, Mascher H, Blomstrand E: Resistance exercise-induced increase in muscle mass correlates with p70S6 kinase phosphorylation in human subjects. Eur J Appl Physiol 2008, 102: 145-152. 10.1007/s00421-007-0564-y

Drummond MJ, Fry CS, Glynn EL, Dreyer HC, Dhanani S, Timmerman KL, Volpi E, Rasmussen BB: Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. J Physiol 2009, 587: 1535-1546. 10.1113/jphysiol.2008.163816

Williamson D, Gallagher P, Harber M, Hollon C, Trappe S: Mitogen-activated protein kinase (MAPK) pathway activation: effects of age and acute exercise on human skeletal muscle. J Physiol 2003, 547: 977-987. 10.1113/jphysiol.2002.036673

Williamson DL, Kubica N, Kimball SR, Jefferson LS: Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle. J Physiol 2006, 573: 497-510. 10.1113/jphysiol.2005.103481

Drummond MJ, Dreyer HC, Pennings B, Fry CS, Dhanani S, Dillon EL, Sheffield-Moore M, Volpi E, Rasmussen BB: Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging. J Appl Physiol 2008, 104: 1452-1461. 10.1152/japplphysiol.00021.2008

Yarasheski KE, Pak-Loduca J, Hasten DL, Obert KA, Brown MB, Sinacore DR: Resistance exercise training increases mixed muscle protein synthesis rate in frail women and men 3 76 yr old. Am J Physiol 1999, 277: E118-125.

Yarasheski KE, Zachwieja JJ, Bier DM: Acute effects of resistance exercise on muscle protein synthesis rate in young and elderly men and women. Am J Physiol 1993, 265: E210-214.

Sheffield-Moore M, Paddon-Jones D, Sanford AP, Rosenblatt JI, Matlock AG, Cree MG, Wolfe RR: Mixed muscle and hepatic derived plasma protein metabolism is differentially regulated in older and younger men following resistance exercise. Am J Physiol Endocrinol Metab 2005, 288: E922-929. 10.1152/ajpendo.00358.2004

Hwee DT, Bodine SC: Age-Related Deficit in Load-Induced Skeletal Muscle Growth. J Gerontol A Biol Sci Med Sci 2009, 64: 618-628.

Bolster DR, Kubica N, Crozier SJ, Williamson DL, Farrell PA, Kimball SR, Jefferson LS: Immediate response of mammalian target of rapamycin (mTOR)-mediated signalling following acute resistance exercise in rat skeletal muscle. J Physiol 2003, 553: 213-220. 10.1113/jphysiol.2003.047019

Koopman R, Zorenc AHG, Gransier RJJ, Cameron-Smith D, van Loon LJC: Increase in S6K1 phosphorylation in human skeletal muscle following resistance exercise occurs mainly in type II muscle fibers. Am J Physiol Endocrinol Metab 2006, 290: E1245-1252. 10.1152/ajpendo.00530.2005

Hornberger TA, Mateja RD, Chin ER, Andrews JL, Esser KA: Aging does not alter the mechanosensitivity of the p38, p70(S6 k), and JNK2 signaling pathways in skeletal muscle. J Appl Physiol 2005, 98: 1562-1566. 10.1152/japplphysiol.00870.2004

Reynolds THt, Bodine SC, Lawrence JC Jr: Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J Biol Chem 2002, 277: 17657-17662. 10.1074/jbc.M201142200

Fluckey JD, Knox M, Smith L, Dupont-Versteegden EE, Gaddy D, Tesch PA, Peterson CA: Insulin-facilitated increase of muscle protein synthesis after resistance exercise involves a MAP kinase pathway. Am J Physiol Endocrinol Metab 2006, 290: E1205-1211. 10.1152/ajpendo.00593.2005

Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, Mueller M, Fumagalli S, Kozma SC, Thomas G: S6K1 (-/-) /S6K2 (-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5 '-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 2004, 24: 3112-3124. 10.1128/MCB.24.8.3112-3124.2004

Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J: RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 2007, 282: 14056-14064. 10.1074/jbc.M700906200

Flotow H, Thomas G: Substrate recognition determinants of the mitogen-activated 70K-S6 kinase from rat liver. J Biol Chem 1992, 267: 3074-3078.

Peterson RT, Schreiber SL: Translation control: Connecting mitogens and the ribosome. Curr Biol 1998, 8: R248-+. 10.1016/S0960-9822(98)70152-6

Jefferies HBJ, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G: Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70(S6 k). Embo J 1997, 16: 3693-3704. 10.1093/emboj/16.12.3693

Fujita S, Rasmussen BB, Cadenas JG, Sattler FR, Volpi E: An acute bout of aerobic exercise restores the physiological response of muscle protein synthesis to insulin in healthy older subjects. FASEB J 2005, 19: A1569-A1569.

Fujita S, Abe T, Drummond MJ, Cadenas JG, Dreyer HC, Sato Y, Volpi E, Rasmussen BB: Blood flow restriction during low-intensity resistance exercise increases S6K1 phosphorylation and muscle protein synthesis. J Appl Physiol 2007, 103: 903-910. 10.1152/japplphysiol.00195.2007

Cuthbertson DJ, Babraj J, Smith K, Wilkes E, Fedele MJ, Esser K, Rennie M: Anabolic signaling and protein synthesis in human skeletal muscle after dynamic shortening or lengthening exercise. Am J Physiol Endocrinol Metab 2006, 290: E731-E738. 10.1152/ajpendo.00415.2005

Karlsson HKR, Nilsson PA, Nilsson J, Chibalin AV, Zierath JR, Blomstrand E: Branched-chain amino acids increase p70(S6 k) phosphorylation in human skeletal muscle after resistance exercise. Am J Physiol Endocrinol Metab 2004, 287: E1-E7. 10.1152/ajpendo.00430.2003

Louis E, Raue U, Yang YF, Jemiolo B, Trappe S: Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J Appl Physiol 2007, 103: 1744-1751. 10.1152/japplphysiol.00679.2007

Dreyer HC, Drummond MJ, Pennings B, Fujita S, Glynn EL, Chinkes DL, Dhanani S, Volpi E, Rasmussen BB: Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. Am J Physiol Endocrinol Metab 2008, 294: E392-E400. 10.1152/ajpendo.00582.2007

Glynn EL, Fry CS, Drummond MJ, Timmerman KL, Dhanani S, Volpi E, Rasmussen BB: Excess leucine intake enhances muscle anabolic signaling but not net protein anabolism in young men and women. J Nutr 2010, 140: 1970-1976. 10.3945/jn.110.127647

Glynn EL, Fry CS, Drummond MJ, Dreyer HC, Dhanani S, Volpi E, Rasmussen BB: 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. 10.1152/ajpregu.00077.2010

Volpi E, Ferrando AA, Yeckel CW, Tipton KD, Wolfe RR: Exogenous amino acids stimulate net muscle protein synthesis in the elderly. J Clin Invest 1998, 101: 2000-2007. 10.1172/JCI939

Volpi E, Kobayashi H, Sheffield-Moore M, Mittendorfer B, Wolfe RR: Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr 2003, 78: 250-258.

Calder AG, Anderson SE, Grant I, McNurlan MA, Garlick PJ: The determination of low D(5)-phenylalanine enrichment (0.002-0.09 atom percent excess), after conversion to phenylethylamine, in relation to protein-turnover studise by gas-chromatography electron ionization mass-spectrometry. Rapid Commun Mass Spectrom 1992, 6: 421-424. 10.1002/rcm.1290060704

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Tập 1 Số 1

Thông tin tác giả