Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age-related anabolic resistance to exercise in humans

Matthew S Brook, Daniel J Wilkinson, William K Mitchell, Jonathan N Lund, Bethan E Phillips, Nathaniel J Szewczyk, Paul L Greenhaff, Kenneth Smith, Philip J Atherton, Matthew S Brook, Daniel J Wilkinson, William K Mitchell, Jonathan N Lund, Bethan E Phillips, Nathaniel J Szewczyk, Paul L Greenhaff, Kenneth Smith, Philip J Atherton

Abstract

Key points: Resistance exercise training (RET) is one of the most effective strategies for preventing declines in skeletal muscle mass and strength with age. Hypertrophic responses to RET with age are diminished compared to younger individuals. In response to 6 weeks RET, we found blunted hypertrophic responses with age are underpinned by chronic deficits in long-term muscle protein synthesis. We show this is likely to be the result of multifactorial deficits in anabolic hormones and blunted translational efficiency and capacity. These results provide great insight into age-related exercise adaptations and provide a platform on which to devise appropriate nutritional and exercise interventions on a longer term basis.

Abstract: Ageing is associated with impaired hypertrophic responses to resistance exercise training (RET). Here we investigated the aetiology of 'anabolic resistance' in older humans. Twenty healthy male individuals, 10 younger (Y; 23 ± 1 years) and 10 older (O; 69 ± 3 years), performed 6 weeks unilateral RET (6 × 8 repetitions, 75% of one repetition maximum (1-RM), 3 times per week). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2 O (70 atom%; thereafter 50 ml week-1 ), further bilateral VL muscle biopsies were taken at 3 and 6 weeks to quantify muscle protein synthesis (MPS) via gas chromatography-pyrolysis-isotope ratio mass spectrometry. After RET, 1-RM increased in Y (+35 ± 4%) and O (+25 ± 3%; P < 0.01), while MVC increased in Y (+21 ± 5%; P < 0.01) but not O (+6 ± 3%; not significant (NS)). In comparison to Y, O displayed blunted RET-induced increases in muscle thickness (at 3 and 6 weeks, respectively, Y: +8 ± 1% and +11 ± 2%, P < 0.01; O: +2.6 ± 1% and +3.5 ± 2%, NS). While 'basal' longer term MPS was identical between Y and O (∼1.35 ± 0.1% day-1 ), MPS increased in response to RET only in Y (3 weeks, Y: 1.61 ± 0.1% day-1 ; O: 1.49 ± 0.1% day-1 ). Consistent with this, O exhibited inferior ribosomal biogenesis (RNA:DNA ratio and c-MYC induction: Y: +4 ± 2 fold change; O: +1.9 ± 1 fold change), translational efficiency (S6K1 phosphorylation, Y: +10 ± 4 fold change; O: +4 ± 2 fold change) and anabolic hormone milieu (testosterone, Y: 367 ± 19; O: 274 ± 19 ng dl-1 (all P < 0.05). Anabolic resistance is thus multifactorial.

Keywords: ageing; exercise; hypertrophy; muscle; protein synthesis; ribosomal biogenesis; signalling; stable isotope.

© 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Figures

Figure 1
Figure 1
Schematic diagram of study protocol
Figure 2. Muscle strength, mass and architecture
Figure 2. Muscle strength, mass and architecture
Time course of changes in T legs as percentage change in 1‐RM from baseline (A), average percentage MVC from baseline (B), thigh fat free mass 0–6 weeks (C), VL MT (D), Lf (E) and θ (F). Values are means ± SEM. aSignificantly different from baseline, P < 0.05; bsignificantly different from previous time point, P < 0.05; csignificantly different from old, P < 0.05. 1‐RM, one repetition maximum; Lf, fibre length; MT, muscle thickness; T, trained; VL, vastus lateralis; θ, pennation angle.
Figure 3. Muscle protein, RNA and DNA…
Figure 3. Muscle protein, RNA and DNA concentrations
Time course of the changes in μg (mg dry weight muscle)−1: ASP (A), RNA (B) and DNA (C); and ratios of ASP:DNA (D), RNA:DNA (E) and RNA:ASP (F). Values are means ± SEM. Significantly different from baseline: *P < 0.05, **P < 0.01; significantly different from old: §P < 0.05. ASP, alkali soluble protein.
Figure 4. Muscle protein synthesis, absolute synthetic…
Figure 4. Muscle protein synthesis, absolute synthetic rate, fractional growth rate and absolute breakdown rate
A, muscle protein synthesis (MPS) rates in UT and T legs in Y and O individuals. B, fractional growth rate (FGR). C, absolute synthetic rate (ASR). D, absolute breakdown rate (ABR). Values are means ± SEM. *Significantly different from UT, P < 0.05. T, trained; UT, untrained.
Figure 5. Intramuscular signalling
Figure 5. Intramuscular signalling
Relative change compared with UT in mTORc1Ser2448 (A), p70S6K1Thr389 (B), rps6ser240/244 (C), ERK1/2Thr202Tyr204 (D), eEF2Thr56 (E), AktSer473 (F), 4EBP1Thr37/46 (G), AMPKThr172 (H), Beclin‐1 (I), Cathepsin L (J), calpain 1 (K), MuRF1 (L), c‐MYC (M), pRBSer780 (N), TIF1a (O), UBF1Ser484 (P), UBF1 (Q), TIF1aSer649 (R). Values are means ± SEM. *Significantly different from UT, P < 0.05. UT, untrained.
Figure 6. Correlations
Figure 6. Correlations
Correlations between RNA:DNA at 3 weeks and MT at 3 weeks (A), RNA:DNA at 6 weeks and TFFM at 6 weeks (B), the increase in P70S6K1T389 after first RET bout and the percentage change in MT at 3 weeks (C), the increase in P70S6K1T389 after first RET bout and the percentage change in TFFM at 6 weeks (D), testosterone after first RET bout and the percentage change in MT at 3 weeks (E), percentage change in testosterone after first RET bout and the percentage change in TFFM at 6 weeks (F), protein intake (g (kg FFM)−1 day−1) and percentage change in MT at 3 weeks (G), and protein intake (g (kg FFM)−1 day−1) and percentage change in TFFM at 6 weeks (H). MT, muscle thickness; RET, resistance exercise trained; TFFM, thigh fat free mass.

References

    1. Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby A, Rankin D, Smith K & Rennie MJ (2010). Muscle full effect after oral protein: Time‐dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. Am J Clin Nutr 92, 1080–1088.
    1. Atherton PJ, Miller BF, Burd NA, et al (2015). Commentaries on Viewpoint: What is the relationship between acute measure of muscle protein synthesis and changes in muscle mass? J Appl Physiol 118, 498–503.
    1. Atherton PJ & Smith K (2012). Muscle protein synthesis in response to nutrition and exercise. J Physiol 590, 1049–1057.
    1. Atherton PJ, Szewczyk NJ, Selby A, Rankin D, Hillier K, Smith K, Rennie MJ & Loughna PT (2009). Cyclic stretch reduces myofibrillar protein synthesis despite increases in FAK and anabolic signalling in L6 cells. J Physiol 587, 3719–3727.
    1. Baar K & Esser K (1999). Phosphorylation of p70(S6k) correlates with increased skeletal muscle mass following resistance J Physiol Cell Physiol 276, C120–C127.
    1. Barton‐Davis ER, Shoturma DI, Musaro A, Rosenthal N & Sweeney HL (1998). Viral mediated expression of insulin‐like growth factor I blocks the aging‐related loss of skeletal muscle function. Proc Natl Acad Sci USA 95, 15603–15607.
    1. Bergen HR, Farr JN, Vanderboom PM, Atkinson EJ, White TA, Singh RJ, Khosla S & LeBrasseur NK (2015). Myostatin as a mediator of sarcopenia versus homeostatic regulator of muscle mass: insights using a new mass spectrometry‐based assay. Skelet Muscle 5, 21.
    1. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A & Casaburi R (1996). The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 335, 1–7.
    1. Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, Phillips J, Sinha‐hikim I, Shen R & Storer TW (2001). Testosterone dose‐response relationships in healthy young men. Am J Physiol Endocrinol Metab 281, E1172–E1181.
    1. Breen L, Stokes KA, Churchward‐Venne TA, Moore DR, Baker SK, Smith K, Atherton PJ & Phillips SM (2013). Two weeks of reduced activity decreases leg lean mass and induces “anabolic resistance” of myofibrillar protein synthesis in healthy elderly. J Clin Endocrinol Metab 98, 2604–2612.
    1. Brook MS, Wilkinson DJ, Mitchell WEEK, Lund JN, Szewczyk NJ, Greenhaff PL, Smith K & Atherton PJ (2015). Skeletal muscle hypertrophy adaptations predominate in the early stages of resistance exercise training, matching deuterium oxide‐derived measures of muscle protein synthesis and mechanistic target of rapamycin complex 1 signaling. FASEB J 29, 4485–4496.
    1. Bukhari SS, Phillips BE, Wilkinson DJ, Limb MC, Rankin D, Mitchell WEEK, Koboyashi H, Greenhaff PL, Smith K & Atherton PJ (2015). Intake of low‐dose leucine‐rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women, at rest and after exercise. Am J Physiol Endocrinol Metab 308, E1056–E1065.
    1. Campbell MJ, McComas AJ & Petito F (1973). Physiological changes in ageing muscles. J Neurol Neurosurg Psychiatry 36, 174–182.
    1. Chesley A, MacDougall JD, Tarnopolsky MA, Atkinson SA & Smith K (1992). Changes in human muscle protein synthesis after resistance exercise. J Appl Physiol 73, 1383–1388.
    1. Christensen K, Doblhammer G, Rau R & Vaupel JW (2009). Ageing populations: the challenges ahead. Lancet 374, 1196–1208.
    1. Coffey VG, Zhong Z, Shield A, Canny BJ, Chibalin AV, Zierath JR & Hawley JA (2006). Early signaling responses to divergent exercise stimuli in skeletal muscle from well‐trained humans. FASEB J 20, 190–192.
    1. Crossland H, Kazi AA, Lang CH, Timmons JA, Pierre P, Wilkinson DJ, Smith K, Szewczyk NJ & Atherton PJ (2013). Focal adhesion kinase is required for IGF‐I‐mediated growth of skeletal muscle cells via a TSC2/mTOR/S6K1‐associated pathway. Am J Physiol Endocrinol Metab 305, E183–E193.
    1. Cuthbertson D, Smith K, Babraj J, Leese G, Waddell T, Atherton P, Wackerhage H, Taylor PM & Rennie MJ (2005). Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J 19, 422–424.
    1. Dietrichson P, Coakley J, Smith PE, Griffiths RD, Helliwell TR & Edwards RH (1987). Conchotome and needle percutaneous biopsy of skeletal muscle. J Neurol Neurosurg Psychiatry 50, 1461–1467.
    1. Dipietro L (2001). Physical activity in aging: changes in patterns and their relationship to health and function. J Gerontol A Biol Sci Med Sci 56, 13–22.
    1. Drummond MJ, Fry CS, Glynn EL, Dreyer HC, Dhanani S, Timmerman KL, Volpi E & Rasmussen BB (2009). Rapamycin administration in humans blocks the contraction‐induced increase in skeletal muscle protein synthesis. J Physiol 587, 1535–1546.
    1. Esmarck B, Andersen JL, Olsen S, Richter EA, Mizuno M & Kjær M (2001). Timing of postexercise protein intake is important for muscle hypertrophy with resistance training in elderly humans. J Physiol 535, 301–311.
    1. Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ & McKinlay JB (2002). Age trends in the level of serum testosterone and other hormones in middle‐aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 87, 589–598.
    1. Fiatarone MA, O'Neill EF, Ryan ND, Clements KM, Solares GR, Nelson ME, Roberts SB, Kehayias JJ, Lipsitz LA & Evans WJ (1994). Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med 330, 1769–1775.
    1. Figueiredo VC, Caldow MK, Massie V, Markworth JF, Cameron‐Smith D & Blazevich AJ (2015). Ribosome biogenesis adaptation in resistance training‐induced human skeletal muscle hypertrophy. Am J Physiol Endocrinol Metab 309, E72–E83.
    1. Figueiredo VC, Roberts LA, Markworth JF, Barnett MPG, Coombes JS, Raastad T, Peake JM & Cameron‐Smith D (2016). Impact of resistance exercise on ribosome biogenesis is acutely regulated by post‐exercise recovery strategies. Physiol Rep 4, e12670.
    1. Fragala MS, Fukuda DH, Stout JR, Townsend JR, Emerson NS, Boone CH, Beyer KS, Oliveira LP & Hoffman JR (2014). Muscle quality index improves with resistance exercise training in older adults. Exp Gerontol 53, 1–6.
    1. Fragala MS, Kenny AM & Kuchel GA (2015). Muscle quality in aging: a multi‐dimensional approach to muscle functioning with applications for treatment. Sport Med 45, 641–658.
    1. Franchi MV, Atherton PJ, Reeves ND, Flück M, Williams J, Mitchell WEEK, Selby A, Beltran Valls RM & Narici MV (2014). Architectural, functional and molecular responses to concentric and eccentric loading in human skeletal muscle. Acta Physiol (Oxf) 210, 642–654.
    1. Fry CS, Drummond MJ, Glynn EL, Dickinson JM, Gundermann DM, Timmerman KL, Walker DK, Dhanani S, Volpi E & Rasmussen BB (2011). Aging impairs contraction‐induced human skeletal muscle mTORC1 signaling and protein synthesis. Skelet Muscle 1, 11.
    1. Fry CS, Drummond MJ, Glynn EL, Dickinson JM, Gundermann DM, Timmerman KL, Walker DK, Volpi E & Rasmussen BB (2013). Skeletal muscle autophagy and protein breakdown following resistance exercise are similar in younger and older adults. J Gerontol A Biol Sci Med Sci 68, 599–607.
    1. Gonzalez AM, Hoffman JR, Jajtner AR, Townsend JR, Boone CH, Beyer KS, Baker KM, Wells AJ, Church DD, Mangine GT, Oliveira LP, Moon JR, Fukuda DH & Stout JR (2015). Protein supplementation does not alter intramuscular anabolic signaling or endocrine response after resistance exercise in trained men. Nutr Res 35, 990–1000.
    1. Greig CA, Gray C, Rankin D, Young A, Mann V, Noble B & Atherton PJ (2011). Blunting of adaptive responses to resistance exercise training in women over 75y. Exp Gerontol 46, 884–890.
    1. Häkkinen K, Kallinen M, Izquierdo M, Jokelainen K, Lassila H, Mälkiä E, Kraemer WJ, Newton RU & Alen M (1998. a). Changes in agonist‐antagonist EMG, muscle CSA, and force during strength training in middle‐aged and older people. J Appl Physiol 84, 1341–1349.
    1. Häkkinen K, Newton RU, Gordon SE, McCormick M, Volek JS, Nindl BC, Gotshalk LA, Campbell WW, Evans WJ, Häkkinen A, Humphries BJ & Kraemer WJ (1998. b). Changes in muscle morphology, electromyographic activity, and force production characteristics during progressive strength training in young and older men. J Gerontol A Biol Sci Med Sci 53, B415–B423.
    1. Hildreth KL, Barry DW, Moreau KL, Vande Griend J, Meacham RB, Nakamura T, Wolfe P, Kohrt WM, Ruscin JM, Kittelson J, Cress ME, Ballard R & Schwartz RS (2013). Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low‐normal testosterone levels. J Clin Endocrinol Metab 98, 1891–1900.
    1. Janssen I, Heymsfield SB, Wang ZM & Ross R (2000). Skeletal muscle mass and distribution in 468 men and women aged 18‐88 yr. J Appl Physiol 89, 81–88.
    1. Janssen I, Shepard DS, Katzmarzyk PT & Roubenoff R (2004). The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc 52, 80–85.
    1. Kirby TJ, Lee JD, England JH, Chaillou T, Esser KA & McCarthy JJ (2015). Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis. J Appl Physiol 119, 321–327.
    1. Kosek DJ, Kim J, Petrella JK, Cross JM, Bamman MM, David J & James M (2006). Efficacy of 3 days/week resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults. J Appl Physiol 101, 531–544.
    1. Kraemer WJ, Häkkinen K, Newton RU, Nindl BC, Volek JS, McCormick M, Gotshalk LA, Gordon SE, Fleck SJ, Campbell WW, Putukian M & Evans WJ (1999). Effects of heavy‐resistance training on hormonal response patterns in younger vs. older men. J Appl Physiol 87, 982–992.
    1. Krogh‐Madsen R, Thyfault JP, Broholm C, Mortensen OH, Olsen RH, Mounier R, Plomgaard P, van Hall G, Booth FW & Pedersen BK (2010). A 2 week reduction of ambulatory activity attenuates peripheral insulin sensitivity. J Appl Physiol 108, 1034–1040.
    1. Kumar V, Atherton PJ, Selby A, Rankin D, Williams J, Smith K, Hiscock N & Rennie MJ (2012). Muscle protein synthetic responses to exercise: effects of age, volume, and intensity. J Gerontol A Biol Sci Med Sci 67, 1170–1177.
    1. Kumar V, Atherton P, Smith K & Rennie MJ (2009. a). Human muscle protein synthesis and breakdown during and after exercise. J Appl Physiol 106, 2026–2039.
    1. Kumar V, Selby A, Rankin D, Patel R, Atherton P, Hildebrandt W, Williams J, Smith K, Seynnes O, Hiscock N & Rennie MJ (2009. b). Age‐related differences in the dose‐response relationship of muscle protein synthesis to resistance exercise in young and old men. J Physiol 587, 211–217.
    1. Kusnadi EP, Hannan KM, Hicks RJ, Hannan RD, Pearson RB & Kang J (2015). Regulation of rDNA transcription in response to growth factors, nutrients and energy. Gene 556, 27–34.
    1. Kvorning T, Andersen M, Brixen K & Madsen K (2006). Suppression of endogenous testosterone production attenuates the response to strength training: a randomized, placebo‐controlled, and blinded intervention study. Am J Physiol Endocrinol Metab 291, E1325–E1332.
    1. Kvorning T, Christensen LL, Madsen K, Nielsen JL, Gejl KD, Brixen K & Andersen M (2013). Mechanical muscle function and lean body mass during supervised strength training and testosterone therapy in aging men with low‐normal testosterone levels. J Am Geriatr Soc 61, 957–962.
    1. Laukkanen PIA, Heikkinen E & Kauppinen M (1995). Muscle strength and mobility as predictors of survival in 75‐84‐year‐old people. Age Ageing 24, 468–473.
    1. Laurent GJ & Sparrow MP (1977). Changes in RNA, DNA and protein content and the rates of protein synthesis and degradation during hypertrophy of the anterior latissimus dorsi muscle of the adult fowl (Gallus domesticus). Growth 41, 249–262.
    1. Laurent GJ, Sparrow MP, Bates PC & Millward DJ (1978). Turnover of muscle protein in the fowl (Gallus domesticus). Rates of protein synthesis in fast and slow skeletal, cardiac and smooth muscle of the adult fowl. Biochem J 176, 419–427.
    1. Leifke E, Gorenoi V, Wichers C & Von Mu A (2000). Age‐related changes of serum sex hormones, insulin‐like growth factor‐1 and sex‐hormone binding globulin levels in men: cross‐sectional data from a healthy male cohort. Clin Endocrinol (Oxf) 53, 689–695.
    1. Luukinen H, Koski K & Laippala P (1997). Factors predicting fractures during falling impacts among home‐dwelling older adults. J Am Geriatr Soc 45, 1302–1309.
    1. Marengoni A, Angleman S, Melis R, Mangialasche F, Karp A, Garmen A, Meinow B & Fratiglioni L (2011). Aging with multimorbidity: A systematic review of the literature. Ageing Res Rev 10, 430–439.
    1. Masel MC, Graham JE, Reistetter TA, Markides KS & Ottenbacher KJ (2009). Frailty and health related quality of life in older Mexican Americans. Health Qual Life Outcomes 7, 70.
    1. Mayhew DL, Kim J, Cross JM, Ferrando AA & Bamman MM (2009). Translational signaling responses preceding resistance training‐mediated myofiber hypertrophy in young and old humans. J Appl Physiol 107, 1655–1662.
    1. Mero AA, Hulmi JJ, Salmijärvi H, Katajavuori M, Haverinen M, Holviala J, Ridanpää T, Häkkinen K, Kovanen V, Ahtiainen JP & Selänne H (2013). Resistance training induced increase in muscle fiber size in young and older men. Eur J Appl Physiol 113, 641–650.
    1. Miller BF, Olesen JL, Hansen M, Døssing S, Crameri RM, Welling RJ, Langberg H, Flyvbjerg A, Kjaer M, Babraj JA, Smith K & Rennie MJ (2005). Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise. J Physiol 567, 1021–1033.
    1. Mitchell CJ, Churchward‐Venne TA, Parise G, Bellamy L, Baker SK, Smith K, Atherton PJ & Phillips SM (2014). Acute post‐exercise myofibrillar protein synthesis is not correlated with resistance training‐induced muscle hypertrophy in young men. PLoS One 9, e89431.
    1. Mitchell WEEK, Williams J, Atherton P, Larvin M, Lund J & Narici M (2012). Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol 3, 260.
    1. Moore DR, Churchward‐Venne TA, Witard O, Breen L, Burd NA, Tipton KD & Phillips SM (2015). Protein ingestion to stimulate myofibrillar protein synthesis requires greater relative protein intakes in healthy older versus younger men. J Gerontol A Biol Sci Med Sci 70, 57–62.
    1. Moore DR, Tang JE, Burd NA, Rerecich T, Tarnopolsky MA & Phillips SM (2009). Differential stimulation of myofibrillar and sarcoplasmic protein synthesis with protein ingestion at rest and after resistance exercise. J Physiol 587, 897–904.
    1. Morley JE (2012). Undernutrition in older adults. Fam Pract; 29 (Suppl 1), i89–i93.
    1. Murton AJ, Billeter R, Stephens FB, Des Etages SG, Graber F, Hill RJ, Marimuthu K & Greenhaff PL (2014). Transient transcriptional events in human skeletal muscle at the outset of concentric resistance exercise training. J Appl Physiol 116, 113–125.
    1. Nader GA, von Walden F, Liu C, Lindvall J, Gutmann L, Pistilli EE & Gordon PM (2014). Resistance exercise training modulates acute gene expression during human skeletal muscle hypertrophy. J Appl Physiol 116, 693–702.
    1. Neto WEEK, Gama EF, Rocha LY, Ramos CC, Taets W, Scapini KB, Ferreira JB, Rodrigues B & Caperuto É (2015). Effects of testosterone on lean mass gain in elderly men: systematic review with meta‐analysis of controlled and randomized studies. Age (Dordr) 37, 9742.
    1. Ogasawara R, Kobayashi K, Tsutaki A, Lee K, Abe T, Fujita S, Nakazato K & Ishii N (2013). mTOR signaling response to resistance exercise is altered by chronic resistance training and detraining in skeletal muscle. J Appl Physiol 114, 934–940.
    1. Olsen RH, Krogh‐Madsen R, Thomsen C, Booth FW & Pedersen BK (2008). Metabolic responses to reduced daily steps in healthy nonexercising men. JAMA 299, 1261–1263.
    1. Peterson M, Rhea M, Sen A & Gordon P (2010). Resistance exercise for muscular strength in older adults: a meta‐analysis mark. Ageing Res Rev 9, 226–237.
    1. Peterson M, Sen A & Gordon P (2011). Influence of resistance exercise on lean body mass in ageing adults: A meta‐analysis. Sci Sport Exerc 43, 249–258.
    1. Phillips B, Williams J, Atherton P, Smith K, Hildebrandt W, Rankin D, Greenhaff P, Macdonald I & Rennie MJ (2012). Resistance exercise training improves age‐related declines in leg vascular conductance and rejuvenates acute leg blood flow responses to feeding and exercise. J Appl Physiol 112, 347–353.
    1. Phillips SM, Tipton KD, Aarsland A, Wolf SE, Wolfe RR & Wolf E (1997). Mixed muscle protein synthesis and breakdown after resistance exercise in humans. Am J Physiol Endocrinol Metab 273, E99–E107.
    1. Raue U, Slivka D, Jemiolo B, Hollon C & Trappe S (2007). Proteolytic gene expression differs at rest and after resistance exercise between young and old women. J Gerontol A Biol Sci Med Sci 62, 1407–1412.
    1. Robinson MM, Turner SM, Hellerstein MK, Hamilton KL & Miller BF (2011). Long‐term synthesis rates of skeletal muscle DNA and protein are higher during aerobic training in older humans than in sedentary young subjects but are not altered by protein supplementation. FASEB J 25, 3240–3249.
    1. Sattler FR, Castaneda‐Sceppa C, Binder EF, Schroeder ET, Wang Y, Bhasin S, Kawakubo M, Stewart Y, Yarasheski KE, Ulloor J, Colletti P, Roubenoff R & Azen SP (2009). Testosterone and growth hormone improve body composition and muscle performance in older men. J Clin Endocrinol Metab 94, 1991–2001.
    1. Scanlon TC, Fragala MS, Stout JR, Emerson NS, Beyer KS, Oliveira LP & Hoffman JR (2014). Muscle architecture and strength: adaptations to short‐term resistance training in older adults. Muscle Nerve 49, 584–592.
    1. Schmittgen TD & Livak KJ (2008). Analyzing real‐time PCR data by the comparative CT method. Nat Protoc 3, 1101–1108.
    1. Schrack JA, Zipunnikov V, Goldsmith J, Bai J, Simonsick EM, Crainiceanu C & Ferrucci L (2014). Assessing the “physical cliff”: detailed quantification of age‐related differences in daily patterns of physical activity. J Gerontol A Biol Sci Med Sci 69, 973–979.
    1. Smith GI, Atherton P, Reeds DN, Mohammed BS, Rankin D, Rennie MJ & Mittendorfer B (2011). Omega‐3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia‐hyperaminoacidaemia in healthy young and middle‐aged men and women. Clin Sci (Lond) 121, 267–278.
    1. Stec MJ, Mayhew DL & Bamman MM (2015). The effects of age and resistance loading on skeletal muscle ribosome biogenesis. J Appl Physiol 119, 851–857.
    1. Stefanetti RJ, Zacharewicz E, Della Gatta P, Garnham A, Russell AP & Lamon S (2014). Ageing has no effect on the regulation of the ubiquitin proteasome‐related genes and proteins following resistance exercise. Front Physiol 5, 30.
    1. Tracy BL, Ivey FM, Hurlbut D, Martel GF, Lemmer JT, Siegel EL, Metter EJ, Fozard JL, Fleg JL & Hurley BF (1999). Muscle quality. II. Effects of strength training in 65‐ to 75‐yr‐old men and women. J Appl Physiol 86, 195–201.
    1. Troiando RP, Berrigan D, Dodd KW, Mâsse LC, Ti Tilert & Mcdoweell M (2008). Physical activity in the United States measured by accelerometer. Med Sci Sport Exerc 40, 181–188.
    1. Tzankoff SP & Norris AH (1977). Effect of muscle mass decrease on age‐related BMR changes. J Appl Physiol 43, 1001–1006.
    1. Verdijk LB, Jonkers RA, Gleeson BG, Beelen M, Meijer K, Savelberg HH, Wodzig WEEK, Dendale P & van Loon LJ (2009). Protein supplementation before and after exercise does not further augment skeletal muscle hypertrophy after resistance training in elderly men. Am J Clin Nutr 89, 608–616.
    1. Volpi E, Sheffield‐Moore M, Rasmussen BB & Wolfe RR (2001). Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA 286, 1206–1212.
    1. Wall BT, Gorissen SH, Pennings B, Koopman R, Groen BBL, Verdijk LB & Van Loon LJC (2015). Aging is accompanied by a blunted muscle protein synthetic response to protein ingestion. PLoS One 10, 1–13.
    1. Waterlow JC, Garlick PJ & Millward DJ (1978). Protein Turnover in Mammalian Tissues and in the Whole Body. Elsevier/North Holland, Amsterdam.
    1. Welinder C & Ekblad L (2011). Coomassie staining as loading control in Western blot analysis. J Proteome Res 10, 1416–1419.
    1. Welle S, Totterman S & Thornton C (1996). Effect of age on muscle hypertrophy induced by resistance training. J Gerontol A Biol Sci Med Sci 51, M270–M275.
    1. West DWD, Baehr LM, Marcotte GR, Chason CM, Tolento L, Gomes AV, Bodine SC & Baar K (2016). Acute resistance exercise activates rapamycin‐sensitive and insensitive mechanisms that control translational activity and capacity in skeletal muscle. J Physiol 594, 453–468.
    1. Whittemore LA, Song K, Li X, Aghajanian J, Davies M, Girgenrath S, Hill JJ, Jalenak M, Kelley P, Knight A, Maylor R, O'Hara D, Pearson A, Quazi A, Ryerson S, Tan XY, Tomkinson KN, Veldman GM, Widom A, Wright JF, Wudyka S, Zhao L & Wolfman NM (2003). Inhibition of myostatin in adult mice increases skeletal muscle mass and strength. Biochem Biophys Res Commun 300, 965–971.
    1. Wilkinson DJ, Cegielski J, Phillips BE, Boereboom C, Lund JN, Atherton PJ & Smith K (2015). Internal comparison between deuterium oxide (D2O) and L‐[ring‐13C6] phenylalanine for acute measurement of muscle protein synthesis in humans. Physiol Rep 3, e12433.
    1. Wilkinson DJ, Franchi MV, Brook MS, Narici MV, Williams JP, Mitchell WEEK, Szewczyk NJ, Greenhaff PL, Atherton PJ & Smith K (2014). A validation of the application of D2O stable isotope tracer techniques for monitoring day‐to‐day changes in muscle protein subfraction synthesis in humans. Am J Physiol Endocrinol Metab 306, E571–E579.
    1. Yarasheski KE, Bhasin S, Sinha‐Hikim I, Pak‐Loduca J & Gonzalez‐Cadavid NF (2002). Serum myostatin‐immunoreactive protein is increased in 60‐92 year old women and men with muscle wasting. J Nutr Health Aging 6, 343–348.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever