MTOR signaling and ubiquitin-proteosome gene expression in the preservation of fat free mass following high protein, calorie restricted weight loss

Nutrition & Metabolism

Peter M Clifton³  Thomas P Wycherley¹  Cassandra M McIver² 

[1] Sansom Institute for Health Research, University of South Australia, Adelaide, Australia;Commonwealth Scientific and Industrial Research Organisation (CSIRO), Food and Nutritional Sciences, PO Box 10041, Adelaide, Australia;Baker IDI, South Australia, Australia

关键词: MuRF-1;    MTORC1;    Skeletal muscle;    Caloric restriction;    Fat free mass;    High protein diet;   

Others  :  812102
DOI  :  10.1186/1743-7075-9-83

 received in 2012-03-27, accepted in 2012-08-27,  发布年份 2012

【 摘 要 】

Caloric restriction is one of the most efficient ways to promote weight loss and is known to activate protective metabolic pathways. Frequently reported with weight loss is the undesirable consequence of fat free (lean muscle) mass loss. Weight loss diets with increased dietary protein intake are popular and may provide additional benefits through preservation of fat free mass compared to a standard protein, high carbohydrate diet. However, the precise mechanism by which a high protein diet may mitigate dietary weight loss induced reductions in fat free mass has not been fully elucidated. Maintenance of fat free mass is dependent upon nutrient stimulation of protein synthesis via the mTOR complex, although during caloric restriction a decrease (atrophy) in skeletal muscle may be driven by a homeostatic shift favouring protein catabolism. This review evaluates the relationship between the macronutrient composition of calorie restricted diets and weight loss using metabolic indicators. Specifically we evaluate the effect of increased dietary protein intake and caloric restricted diets on gene expression in skeletal muscle, particularly focusing on biosynthesis, degradation and the expression of genes in the ubiquitin-proteosome (UPP) and mTOR signaling pathways, including MuRF-1, MAFbx/atrogin-1, mTORC1, and S6K1.

【 授权许可】

   
2012 McIver et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Brinkworth GD, Noakes M, Clifton PM, Buckley JD: Effects of a Low Carbohydrate Weight Loss Diet on Exercise Capacity and Tolerance in Obese Subjects. 2009. [Obesity (Silver Spring)]
• [2]Utzschneider KM, Carr DB, Barsness SM, Kahn SE, Schwartz RS: Diet-induced weight loss is associated with an improvement in beta-cell function in older men. J Clin Endocrinol Metab 2004, 89:2704-2710.
• [3]Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD, Sullivan M, Wedel H: Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004, 351:2683-2693.
• [4]Marquez-Quinones A, Mutch DM, Debard C, Wang P, Combes M, Roussel B, Holst C, Martinez JA, Handjieva-Darlenska T, Kalouskova P, Jebb S, Babalis D, Pfeiffer AF, Larsen TM, Astrup A, Saris WH, Mariman E, Clement K, Vidal H, Langin D, Viguerie N: Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake. Am J Clin Nutr 2010, 92:975-984.
• [5]Stiegler P, Cunliffe A: The role of diet and exercise for the maintenance of fat-free mass and resting metabolic rate during weight loss. Sports Med 2006, 36:239-262.
• [6]Manders RJ, Koopman R, Beelen M, Gijsen AP, Wodzig WK, Saris WH, van Loon LJ: The Muscle Protein Synthetic Response to Carbohydrate and Protein Ingestion Is Not Impaired in Men with Longstanding Type 2 Diabetes. J Nutr 2008, 138:1079-1085.
• [7]Wolfe RR: The underappreciated role of muscle in health and disease. Am J Clin Nutr 2006, 84:475-482.
• [8]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.
• [9]Bohe J, Low JF, Wolfe RR, Rennie MJ: Latency and duration of stimulation of human muscle protein synthesis during continuous infusion of amino acids. J Physiol 2001, 532:575-579.
• [10]Phillips SM, Hartman JW, Wilkinson SB: Dietary protein to support anabolism with resistance exercise in young men. J Am Coll Nutr 2005, 24:134S-139S.
• [11]Laplante M, Sabatini DM: mTOR signaling in growth control and disease. Cell 2012, 149:274-293.
• [12]Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB: Insulin resistance due to nutrient excess: Is it a consequence of AMPK downregulation? Cell Cycle 2011, 10:3447-3451.
• [13]Garlick PJ, McNurlan MA, Ballmer PE: Influence of dietary protein intake on whole-body protein turnover in humans. Diabetes Care 1991, 14:1189-1198.
• [14]Villareal DT, Smith GI, Shah K, Mittendorfer B: Effect of Weight Loss on the Rate of Muscle Protein Synthesis During Fasted and Fed Conditions in Obese Older Adults. 2011. [Obesity (Silver Spring)]
• [15]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.
• [16]Moore DL, Robinson MJ, Fry JL, Tang JE, Glover EI, Wilkinson S, Prior T, Tarnopolsky MA, Phillips SM: Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in young men. Am J Clin Nutr 2009, 89:161-168.
• [17]Slater G, Phillips SM: Nutrition guidelines for strength sports: sprinting, weightlifting, throwing events, and bodybuilding. J Sports Sci 2011, 29(Suppl 1):S67-77.
• [18]Tang JE, Moore DR, Kujbida GW, Tarnopolsky MA, Phillips SM: Ingestion of whey hydrolysate, casein, or soy protein isolate: effects on mixed muscle protein synthesis at rest and following resistance exercise in young men. J Appl Physiol 2009, 107:987-992.
• [19]Tang JE, Phillips SM: Maximizing muscle protein anabolism: the role of protein quality. Curr Opin Clin Nutr Metab Care 2009, 12:66-71.
• [20]Baba NH, Sawaya S, Torbay N, Habbal Z, Azar S, Hashim SA: High protein vs high carbohydrate hypoenergetic diet for the treatment of obese hyperinsulinemic subjects. Int J Obes Relat Metab Disord 1999, 23:1202-1206.
• [21]Evangelista LS, Heber D, Li Z, Bowerman S, Hamilton MA, Fonarow GC: Reduced body weight and adiposity with a high-protein diet improves functional status, lipid profiles, glycemic control, and quality of life in patients with heart failure: a feasibility study. J Cardiovasc Nurs 2009, 24:207-215.
• [22]Flechtner-Mors M, Boehm BO, Wittmann R, Thoma U, Ditschuneit HH: Enhanced weight loss with protein-enriched meal replacements in subjects with the metabolic syndrome. Diabetes Metab Res Rev 2010, 26:393-405.
• [23]Labayen I, Diez N, Gonzalez A, Parra D, Martinez JA: Effects of protein vs. carbohydrate-rich diets on fuel utilisation in obese women during weight loss. Forum Nutr 2003, 56:168-170.
• [24]Lasker DA, Evans EM, Layman DK: Moderate carbohydrate, moderate protein weight loss diet reduces cardiovascular disease risk compared to high carbohydrate, low protein diet in obese adults: a randomized clinical trial. Nutr Metab (Lond) 2008, 5:30. BioMed Central Full Text
• [25]Noakes M, Keogh JB, Foster PR, Clifton PM: Effect of an energy-restricted, high-protein, low-fat diet relative to a conventional high-carbohydrate, low-fat diet on weight loss, body composition, nutritional status, and markers of cardiovascular health in obese women. Am J Clin Nutr 2005, 81:1298-1306.
• [26]Clifton PM, Bastiaans K, Keogh JB: High protein diets decrease total and abdominal fat and improve CVD risk profile in overweight and obese men and women with elevated triacylglycerol. Nutr Metab Cardiovasc Dis 2009, 19:548-554.
• [27]Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT: Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Am J Clin Nutr 2006, 83:1025-1031. quiz 1205
• [28]Farnsworth E, Luscombe ND, Noakes M, Wittert G, Argyiou E, Clifton PM: Effect of a high-protein, energy-restricted diet on body composition, glycemic control, and lipid concentrations in overweight and obese hyperinsulinemic men and women. Am J Clin Nutr 2003, 78:31-39.
• [29]Layman DK, Boileau RA, Erickson DJ, Painter JE, Shiue H, Sather C, Christou DD: A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women. J Nutr 2003, 133:411-417.
• [30]Leidy HJ, Carnell NS, Mattes RD, Campbell WW: Higher protein intake preserves lean mass and satiety with weight loss in pre-obese and obese women. Obesity (Silver Spring) 2007, 15:421-429.
• [31]Piatti PM, Monti F, Fermo I, Baruffaldi L, Nasser R, Santambrogio G, Librenti MC, Galli-Kienle M, Pontiroli AE, Pozza G: Hypocaloric high-protein diet improves glucose oxidation and spares lean body mass: comparison to hypocaloric high-carbohydrate diet. Metabolism 1994, 43:1481-1487.
• [32]Kleiner RE, Hutchins AM, Johnston CS, Swan PD: Effects of an 8-week high-protein or high-carbohydrate diet in adults with hyperinsulinemia. MedGenMed 2006, 8:39.
• [33]Luscombe ND, Clifton PM, Noakes M, Farnsworth E, Wittert G: Effect of a high-protein, energy-restricted diet on weight loss and energy expenditure after weight stabilization in hyperinsulinemic subjects. Int J Obes Relat Metab Disord 2003, 27:582-590.
• [34]Stamets K, Taylor DS, Kunselman A, Demers LM, Pelkman CL, Legro RS: A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome. Fertil Steril 2004, 81:630-637.
• [35]Kasim-Karakas SE, Almario RU, Cunningham W: Effects of protein versus simple sugar intake on weight loss in polycystic ovary syndrome (according to the National Institutes of Health criteria). Fertil Steril 2009, 92:262-270.
• [36]Parker B, Noakes M, Luscombe N, Clifton P: Effect of a high-protein, high-monounsaturated fat weight loss diet on glycemic control and lipid levels in type 2 diabetes. Diabetes Care 2002, 25:425-430.
• [37]Treyzon L, Chen S, Hong K, Yan E, Carpenter CL, Thames G, Bowerman S, Wang HJ, Elashoff R, Li Z: A controlled trial of protein enrichment of meal replacements for weight reduction with retention of lean body mass. Nutr J 2008, 7:23. BioMed Central Full Text
• [38]Torbay N, Baba NH, Sawaya S, Bajjani R, Habbal Z, Azar S, Hashim SA: High protein vs high carbohydrate hypoenergetic diet in treatment of obese normoinsulinemic and hyperinsulinemic subjects. Nutr Res 2002, 22:587-598.
• [39]Feinman RD, Fine EJ: Thermodynamics and metabolic advantage of weight loss diets. Metab Syndr Relat Disord 2003, 1:209-219.
• [40]Veldhorst MA, Westerterp-Plantenga MS, Westerterp KR: Gluconeogenesis and energy expenditure after a high-protein, carbohydrate-free diet. Am J Clin Nutr 2009, 90:519-526.
• [41]Soenen S, Westerterp-Plantenga MS: Changes in body fat percentage during body weight stable conditions of increased daily protein intake vs. control. Physiol Behav 2010, 101:635-638.
• [42]Linn T, Geyer R, Prassek S, Laube H: Effect of dietary protein intake on insulin secretion and glucose metabolism in insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1996, 81:3938-3943.
• [43]Linn T, Santosa B, Gronemeyer D, Aygen S, Scholz N, Busch M, Bretzel RG: Effect of long-term dietary protein intake on glucose metabolism in humans. Diabetologia 2000, 43:1257-1265.
• [44]Chaston TB, Dixon JB, O'Brien PE: Changes in fat-free mass during significant weight loss: a systematic review. Int J Obes (Lond) 2007, 31:743-750.
• [45]Ravussin E, Lillioja S, Knowler WC, Christin L, Freymond D, Abbott WGH, Boyce V, Howard BV, Bogardus C: Reduced Rate of Energy-Expenditure as a Risk Factor for Body-Weight Gain. 1988, 318:467-472.
• [46]Westerterp-Plantenga MS, Lejeune MP, Nijs I, van Ooijen M, Kovacs EM: High protein intake sustains weight maintenance after body weight loss in humans. Int J Obes Relat Metab Disord 2004, 28:57-64.
• [47]Pasman WJ, Saris WH, Muls E, Vansant G, Westerterp-Plantenga MS: Effect of exercise training on long-term weight maintenance in weight-reduced men. Metabolism 1999, 48:15-21.
• [48]Beavers KM, Lyles MF, Davis CC, Wang X, Beavers DP, Nicklas BJ: Is lost lean mass from intentional weight loss recovered during weight regain in postmenopausal women. Am J Clin Nutr 94:767-774.
• [49]Phillips SK, Rook KM, Siddle NC, Bruce SA, Woledge RC: Muscle weakness in women occurs at an earlier age than in men, but strength is preserved by hormone replacement therapy. Clin Sci (Lond) 1993, 84:95-98.
• [50]Miller SL, Wolfe RR: The danger of weight loss in the elderly. J Nutr Health Aging 2008, 12:487-491.
• [51]Op den Kamp CM, Langen RC, Haegens A, Schols AM: Muscle atrophy in cachexia: can dietary protein tip the balance. Curr Opin Clin Nutr Metab Care 2009, 12:611-616.
• [52]Lejeune MP, Kovacs EM, Westerterp-Plantenga MS: Additional protein intake limits weight regain after weight loss in humans. Br J Nutr 2005, 93:281-289.
• [53]Wackerhage H, Rennie MJ: How nutrition and exercise maintain the human musculoskeletal mass. J Anat 2006, 208:451-458.
• [54]Glass DJ: Skeletal muscle hypertrophy and atrophy signaling pathways. Int J Biochem Cell Biol 2005, 37:1974-1984.
• [55]Hands SL, Proud CG, Wyttenbach A: mTOR's role in ageing: protein synthesis or autophagy? Aging (Albany NY) 2009, 1:586-597.
• [56]Leibowitz G, Cerasi E, Ketzinel-Gilad M: The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes. Diabetes Obes Metab 2008, 10(Suppl 4):157-169.
• [57]Chun KH, Choi KD, Lee DH, Jung Y, Henry RR, Ciaraldi TP, Kim YB: In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes. Am J Physiol Endocrinol Metab 2011, 300:E536-542.
• [58]Ruiz-Alcaraz AJ, Liu HK, Cuthbertson DJ, McManus EJ, Akhtar S, Lipina C, Morris AD, Petrie JR, Hundal HS, Sutherland C: A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration. Biochem J 2005, 392:345-352.
• [59]Kimball SR, Jefferson LS: Control of translation initiation through integration of signals generated by hormones, nutrients, and exercise. J Biol Chem 2010, 285:29027-29032.
• [60]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.
• [61]Drummond MJ, Dreyer HC, Fry CS, Glynn EL, Rasmussen BB: Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling. J Appl Physiol 2009, 106:1374-1384.
• [62]Blagosklonny MV: Calorie restriction: decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle 2010, 9:683-688.
• [63]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.
• [64]Gran P: Anabolic signalling in skeletal muscle : impact of diet and disease. In School of Exercise and Nutrition Sciences, Deakin University; 2011.
• [65]Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM: Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids. Am J Clin Nutr 2005, 81:762-772.
• [66]Franch HA, Price SR: Molecular signaling pathways regulating muscle proteolysis during atrophy. Curr Opin Clin Nutr Metab Care 2005, 8:271-275.
• [67]Glickman MH, Ciechanover A: The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002, 82:373-428.
• [68]Solomon V, Goldberg AL: Importance of the ATP-ubiquitin-proteasome pathway in the degradation of soluble and myofibrillar proteins in rabbit muscle extracts. J Biol Chem 1996, 271:26690-26697.
• [69]Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL: FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007, 6:472-483.
• [70]Lecker SH, Goldberg AL, Mitch WE: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 2006, 17:1807-1819.
• [71]Sacheck JM, Ohtsuka A, McLary SC, Goldberg AL: IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. Am J Physiol Endocrinol Metab 2004, 287:E591-601.
• [72]Kim HJ, Jamart C, Deldicque L, An GL, Lee YH, Kim CK, Raymackers JM, Francaux M: Endoplasmic reticulum stress markers and ubiquitin-proteasome pathway activity in response to a 200-km run. Med Sci Sports Exerc 2011, 43:18-25.
• [73]Ponnappan U: Ubiquitin-proteasome pathway is compromised in CD45RO + and CD45RA + T lymphocyte subsets during aging. Exp Gerontol 2002, 37:359-367.
• [74]Wohlgemuth SE, Seo AY, Marzetti E, Lees HA, Leeuwenburgh C: Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp Gerontol 2010, 45:138-148.
• [75]Selsby JT, Judge AR, Yimlamai T, Leeuwenburgh C, Dodd SL: Life long calorie restriction increases heat shock proteins and proteasome activity in soleus muscles of Fisher 344 rats. Exp Gerontol 2005, 40:37-42.
• [76]Hepple RT, Qin M, Nakamoto H, Goto S: Caloric restriction optimizes the proteasome pathway with aging in rat plantaris muscle: implications for sarcopenia. Am J Physiol Regul Integr Comp Physiol 2008, 295:R1231-1237.
• [77]Jagoe RT, Lecker SH, Gomes M, Goldberg AL: Patterns of gene expression in atrophying skeletal muscles: response to food deprivation. FASEB J 2002, 16:1697-1712.
• [78]Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO: Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 2008, 7:681-687.
• [79]Speakman JR, Mitchell SE: Caloric restriction. Mol Aspects Med 2011, 32:159-221.
• [80]Belobrajdic DP, Frystyk J, Jeyaratnaganthan N, Espelund U, Flyvbjerg A, Clifton PM, Noakes M: Moderate energy restriction-induced weight loss affects circulating IGF levels independent of dietary composition. Eur J Endocrinol 2010, 162:1075-1082.
• [81]Zhu K, Meng X, Kerr DA, Devine A, Solah V, Binns CW, Prince RL: The effects of a two-year randomized, controlled trial of whey protein supplementation on bone structure, IGF-1, and urinary calcium excretion in older postmenopausal women. J Bone Miner Res 2011, 26:2298-2306.
• [82]Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A: Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA 2003, 100:11285-11290.
• [83]de Palma L, Marinelli M, Pavan M, Orazi A: Ubiquitin ligases MuRF1 and MAFbx in human skeletal muscle atrophy. Joint Bone Spine 2008, 75:53-57.
• [84]Wohlgemuth SE, Lees HA, Marzetti E, Manini TM, Aranda JM, Daniels MJ, Pahor M, Perri MG, Leeuwenburgh C, Anton SD: An exploratory analysis of the effects of a weight loss plus exercise program on cellular quality control mechanisms in older overweight women. Rejuvenation Res 2011, 14:315-324.
• [85]Walrand S, Short KR, Bigelow ML, Sweatt AJ, Hutson SM, Nair KS: Functional impact of high protein intake on healthy elderly people. Am J Physiol Endocrinol Metab 2008, 295:E921-928.
• [86]Layman DK: Protein quantity and quality at levels above the RDA improves adult weight loss. J Am Coll Nutr 2004, 23:631S-636S.
• [87]Zemel MB: Proposed role of calcium and dairy food components in weight management and metabolic health. Phys Sportsmed 2009, 37:29-39.
• [88]Layman DK: The role of leucine in weight loss diets and glucose homeostasis. J Nutr 2003, 133:261S-267S.
• [89]Anthony JC, Anthony TG, Kimball SR, Jefferson LS: Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr 2001, 131:856S-860S.
• [90]Kimball SR, Jefferson LS: Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. J Nutr 2006, 136:227S-231S.
• [91]Crozier SJ, Kimball SR, Emmert SW, Anthony JC, Jefferson LS: Oral leucine administration stimulates protein synthesis in rat skeletal muscle. J Nutr 2005, 135:376-382.
• [92]Xu G, Kwon G, Marshall CA, Lin TA, Lawrence JC Jr: McDaniel ML: Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic beta-cells. A possible role in protein translation and mitogenic signaling. J Biol Chem 1998, 273:28178-28184.
• [93]Kimball SR: The role of nutrition in stimulating muscle protein accretion at the molecular level. Biochem Soc Trans 2007, 35:1298-1301.
• [94]Kimball SR, Do AN, Kutzler L, Cavener DR, Jefferson LS: Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis. J Biol Chem 2008, 283:3465-3475.
• [95]Catania C, Binder E, Cota D: mTORC1 signaling in energy balance and metabolic disease. Int J Obes (Lond) 2011, 35:751-761.
• [96]Byfield MP, Murray JT, Backer JM: hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 2005, 280:33076-33082.
• [97]Nobukuni T, Kozma SC: Thomas G: hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr Opin Cell Biol 2007, 19:135-141.
• [98]Um SH, D'Alessio D, Thomas G: Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 2006, 3:393-402.
• [99]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.