HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: 19/3/422 04-2640fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cuthbertson, D. Articles by Rennie, M. J Search for Related Content PubMed PubMed Citation Articles by Cuthbertson, D. Articles by Rennie, M. J

Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle

Daniel Cuthbertson^*,, Kenneth Smith^*,, John Babraj^*, Graham Leese, Tom Waddell^*, Philip Atherton^*,, Henning Wackerhage^*, Peter M Taylor^* and Michael J Rennie^*,,1

^* Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, Scotland;
Department of Medicine, Ninewells Hospital and Medical School, Tayside NHS Trust, Dundee, Scotland;
Department of Biological Sciences, University of Central Lancashire, Preston, UK;
University of Nottingham, School of Biomedical Sciences, Division of Clinical Physiology, Graduate Entry Medical School, City Hospital, Derby, UK

¹Correspondence: University of Nottingham, School of Biomedical Sciences, Division of Clinical Physiology, Graduate Entry Medical School, City Hospital, Derby DE22 3DT, UK. E-mail: michael.rennie{at}nottingham.ac.uk

SPECIFIC AIMS

Healthy aging is associated with wasting of skeletal muscle of unknown cause. We hypothesized that, for lack of good evidence of derangements of muscle protein turnover in the basal, post-absorptive state, the deficit in the muscle maintenance must lie elsewhere, possibly in a diminished response to amino acids, the most anabolically potent of nutrients. We aimed to test this by measuring the responses to mixed oral essential amino acids (EAA) of 1) skeletal muscle protein synthesis (MPS) and 2) components of anabolic signaling pathways in healthy young and elderly men.

PRINCIPAL FINDINGS

We studied 44 young and elderly men (means±SD, respectively: age, 28±1, 70±1 y; body mass index, (BMI), 24±3, 26±4 kg.m^–2; skeletal muscle mass, 33±4, 28±4 kg, P<0.01). We measured the fractional synthetic rates (FSR) of protein in their m. vastus lateralis as the rate of incorporation of [¹³C] leucine from a primed, constant infusion of [1-¹³C]-ketoisocaproic acid, over 3 h after they drank solutions of 0–40 g of mixed essential amino acids (EAA) to obtain dose-response relationships, while clamping plasma insulin and glucose at basal concentrations. Muscle biopsies were taken before and 3 h after EAA.

1. Rates of muscle protein synthesis
Basal rates (MPS) were indistinguishable between the young and elderly (myofibrillar FSR, 0.030±0.005%.h^–1, sarcoplasmic FSR, 0.055±0.007%.h^–1, grand means±SD) but the elderly showed decrements in the anabolic sensitivity of MPS to EAA (Fig. 1 ), which occurred in both groups without any increase in insulin as a result of the clamp. On relating rates of MPS to the plasma availability (i.e., the area under the time curve of its concentration) rather than the dose of leucine, (the possibly regulatory EAA), the differences were magnified (P < 0.001).

View larger version (23K): [in this window] [in a new window]   Figure 1. Relationships in healthy men and elderly men between rates of A) myofibrillar and B) sarcoplasmic protein synthesis in vastus lateralis (determined on the basis of intracellular leucine labeling and time profile of leucine) and dose of essential amino acids (EAA) given orally; and relationships between increase of C) myofibrillar and D) sarcoplasmic protein synthesis above baseline against increase of AUC of plasma leucine above baseline ( AUC); (values are means±SE; *P<0.05, **P<0.05).

2. Protein synthetic capacity
Both RNA: Protein ratio and the ratio of MPS to RNA after ingestion of 10 g of EAA (P<0.001), were less in the elderly, suggesting both reduced capacity and efficiency of MPS.

3. Signaling capacity and activation by EAA and index of inflammation
The concentrations and degree of activation (phosphorylation state) of components of the amino acid sensing/signaling anabolic pathways (mTOR, p70^s6 kinase, eIF4BP-1) were significantly less (–30 to 50%, P<0.01) in the elderly (Fig. 2 ). The concentration of NF-B, a transcription factor associated with inflammation, was 4-fold greater (P<0.01).

View larger version (14K): [in this window] [in a new window]   Figure 2. Quantification after Western analysis of components of anabolic signaling pathways in muscle from young vs. elderly and effects of 10 g EAA on their phosphorylation; (means±SD; *different from basal). Differences after EAA are significantly different between young and old (P<0.05).

CONCLUSIONS AND SIGNIFICANCE

These results demonstrate 1) EAA stimulate MPS independent of an increase in insulin availability; 2) in the elderly, a deficit in MPS in the basal state is unlikely; and 3) the decreased sensitivity and responsiveness of MPS to EAA, associated with decrements in the concentrations and excitability of components of anabolic signaling pathways, are probably major contributors to the failure of muscle maintenance in the elderly, possibly following an increased inflammatory state. These findings provide an explanation for the apparent paradox of ongoing sarcopenia in individuals in whom no apparent deficit of muscle protein synthesis or breakdown could be discerned in the postabsorptive basal state. There is no likely benefit to elderly people of simply increasing daily protein intake (because of their decreased anabolic capacity); nevertheless, a good case exists for consuming foods with a high protein:energy ratio, with most dietary protein being taken during a main meal (ideally after vigorous exercise) to maximize availability in the sensitive range of EAA concentration.

View larger version (31K): [in this window] [in a new window]   Figure 3. The effect of aging on human muscle maintenance and development of sarcopenia.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2640fje;

This article has been cited by other articles:

				D. Paddon-Jones, K. R Short, W. W Campbell, E. Volpi, and R. R Wolfe Role of dietary protein in the sarcopenia of aging Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1562S - 1566S. [Abstract] [Full Text] [PDF]

				D J. Millward, D. K Layman, D. Tome, and G. Schaafsma Protein quality assessment: impact of expanding understanding of protein and amino acid needs for optimal health Am. J. Clinical Nutrition, May 1, 2008; 87(5): 1576S - 1581S. [Abstract] [Full Text] [PDF]

				M. J. Drummond, H. C. Dreyer, B. Pennings, C. S. Fry, S. Dhanani, E. L. Dillon, M. Sheffield-Moore, E. Volpi, and B. B. Rasmussen Skeletal muscle protein anabolic response to resistance exercise and essential amino acids is delayed with aging J Appl Physiol, May 1, 2008; 104(5): 1452 - 1461. [Abstract] [Full Text] [PDF]

				P. J. Morrison, D. Hara, Z. Ding, and J. L. Ivy Adding protein to a carbohydrate supplement provided after endurance exercise enhances 4E-BP1 and RPS6 signaling in skeletal muscle J Appl Physiol, April 1, 2008; 104(4): 1029 - 1036. [Abstract] [Full Text] [PDF]

				H. C. Dreyer, M. J. Drummond, B. Pennings, S. Fujita, E. L. Glynn, D. L. Chinkes, S. Dhanani, E. Volpi, and B. B. Rasmussen 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, February 1, 2008; 294(2): E392 - E400. [Abstract] [Full Text] [PDF]

				M. J Rennie, P. Atherton, A. Selby, K. Smith, M. Narici, M. de Boer, S. Phillips, and E. Glover Letter to the Editor on the Journal Club article by Barker and Traber J. Physiol., January 1, 2008; 586(1): 307 - 308. [Full Text] [PDF]

				J. Escobar, J. W. Frank, A. Suryawan, H. V. Nguyen, and T. A. Davis Amino acid availability and age affect the leucine stimulation of protein synthesis and eIF4F formation in muscle Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1615 - E1621. [Abstract] [Full Text] [PDF]

				M. D. de Boer, A. Selby, P. Atherton, K. Smith, O. R. Seynnes, C. N. Maganaris, N. Maffulli, T. Movin, M. V. Narici, and M. J. Rennie The temporal responses of protein synthesis, gene expression and cell signalling in human quadriceps muscle and patellar tendon to disuse J. Physiol., November 15, 2007; 585(1): 241 - 251. [Abstract] [Full Text] [PDF]

				G. I. Smith, D. T. Villareal, and B. Mittendorfer Measurement of human mixed muscle protein fractional synthesis rate depends on the choice of amino acid tracer Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E666 - E671. [Abstract] [Full Text] [PDF]

				R. Koopman, B. Pennings, A. H. G. Zorenc, and L. J. C. van Loon Protein Ingestion Further Augments S6K1 Phosphorylation in Skeletal Muscle Following Resistance Type Exercise in Males J. Nutr., August 1, 2007; 137(8): 1880 - 1886. [Abstract] [Full Text] [PDF]

				S. Fujita, H. C. Dreyer, M. J. Drummond, E. L. Glynn, J. G. Cadenas, F. Yoshizawa, E. Volpi, and B. B. Rasmussen Nutrient signalling in the regulation of human muscle protein synthesis J. Physiol., July 15, 2007; 582(2): 813 - 823. [Abstract] [Full Text] [PDF]

				M. C Steiner Sarcopaenia in chronic obstructive pulmonary disease Thorax, February 1, 2007; 62(2): 101 - 103. [Full Text] [PDF]

				J. Eliasson, T. Elfegoun, J. Nilsson, R. Kohnke, B. Ekblom, and E. Blomstrand Maximal lengthening contractions increase p70 S6 kinase phosphorylation in human skeletal muscle in the absence of nutritional supply Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1197 - E1205. [Abstract] [Full Text] [PDF]

				R. Koopman, L. Verdijk, R. J. Manders, A. P Gijsen, M. Gorselink, E. Pijpers, A. J. Wagenmakers, and L. J. van Loon Co-ingestion of protein and leucine stimulates muscle protein synthesis rates to the same extent in young and elderly lean men. Am. J. Clinical Nutrition, September 1, 2006; 84(3): 623 - 632. [Abstract] [Full Text] [PDF]

				I. Rieu, M. Balage, C. Sornet, C. Giraudet, E. Pujos, J. Grizard, L. Mosoni, and D. Dardevet Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia J. Physiol., August 15, 2006; 575(1): 305 - 315. [Abstract] [Full Text] [PDF]

				D. M. Thomson and S. E. Gordon Impaired overload-induced muscle growth is associated with diminished translational signalling in aged rat fast-twitch skeletal muscle J. Physiol., July 1, 2006; 574(1): 291 - 305. [Abstract] [Full Text] [PDF]

				R. Koopman, A. H. G. Zorenc, R. J. J. Gransier, D. Cameron-Smith, and L. J. C. van Loon Increase in S6K1 phosphorylation in human skeletal muscle following resistance exercise occurs mainly in type II muscle fibers Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1245 - E1252. [Abstract] [Full Text] [PDF]

				D. J. Cuthbertson, J. Babraj, K. Smith, E. Wilkes, M. J. Fedele, K. Esser, and M. Rennie Anabolic signaling and protein synthesis in human skeletal muscle after dynamic shortening or lengthening exercise Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E731 - E738. [Abstract] [Full Text] [PDF]

				M. J. Rennie, J. Bohe, K. Smith, H. Wackerhage, and P. Greenhaff Branched-Chain Amino Acids as Fuels and Anabolic Signals in Human Muscle J. Nutr., January 1, 2006; 136(1): 264S - 268S. [Abstract] [Full Text] [PDF]

				S. Fujita and E. Volpi Amino Acids and Muscle Loss with Aging J. Nutr., January 1, 2006; 136(1): 277S - 280S. [Abstract] [Full Text] [PDF]

				L. Combaret, D. Dardevet, I. Rieu, M.-N. Pouch, D. Bechet, D. Taillandier, J. Grizard, and D. Attaix A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle J. Physiol., December 1, 2005; 569(2): 489 - 499. [Abstract] [Full Text] [PDF]

				M. J. Rennie A role for leucine in rejuvenating the anabolic effects of food in old rats J. Physiol., December 1, 2005; 569(2): 357 - 357. [Full Text] [PDF]

				P. L Kim, R. S Staron, and S. M Phillips Fasted-state skeletal muscle protein synthesis after resistance exercise is altered with training J. Physiol., October 1, 2005; 568(1): 283 - 290. [Abstract] [Full Text] [PDF]

				M. J Rennie Body maintenance and repair: how food and exercise keep the musculoskeletal system in good shape Exp Physiol, July 1, 2005; 90(4): 427 - 436. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) All Versions of this Article: 19/3/422 04-2640fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cuthbertson, D. Articles by Rennie, M. J Search for Related Content PubMed PubMed Citation Articles by Cuthbertson, D. Articles by Rennie, M. J