Human muscle protein turnover—why is it so variable?

We undertook a comprehensive review of the literature to unravel the nature of the variability in the reported rate of human muscle protein synthesis. We analyzed the results from studies that report the protein fractional synthesis rate (FSR) in the vastus lateralis in healthy, nonobese, untrained adults ≤50 yr of age in the postabsorptive state at rest by using the primed, constant tracer amino acid infusion method according to experimental design characteristics. We hypothesized that if the variability is methodological (rather than physiological) in nature, systematic clustering of FSR values would be evident, and outliers would become apparent. Overall, as expected, the mixed muscle protein FSR values were significantly ( P < 0.001) greater when the muscle vs. the plasma free amino acid enrichment is used as the surrogate precursor pool enrichment, and the average mixed muscle protein FSR values were significantly greater ( P = 0.05) than the myofibrillar/myosin heavy chain FSR values. The within-study variability (i.e., population variance) was somewhat smaller in studies that used plasma amino acid/ketoacid enrichments vs. muscle free amino acid enrichment (∼24 vs. ∼31%), but this was not apparent in all circumstances. Furthermore, the between-study consistency of measured FSR values (i.e., interquartile range) was inversely correlated with the average duration between biopsies. Aside from that, the variation in reported FSR values could not be explained by differences in the experimental design and analytical methods, and none of the most commonly used approaches stood out as clearly superior in terms of consistency of results and/or within-study variability. We conclude that the variability in reported values is in part due to 1) differences in experimental design (e.g., choice of precursor pool) and 2) considerable within-subject variability. The summary of the results from our analysis can be used as guidelines for “normal” average basal FSR values at rest in healthy adults.

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An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.1.e122 ◽

1997 ◽

Vol 273 (1) ◽

pp. E122-E129 ◽

Cited By ~ 168

Author(s):

G. Biolo ◽

K. D. Tipton ◽

S. Klein ◽

R. R. Wolfe

Keyword(s):

Amino Acids ◽

Blood Flow ◽

Protein Synthesis ◽

Amino Acid ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Amino Acid Mixture ◽

Acid Mixture ◽

Protein Kinetics ◽

Amino Acid Infusion

Six normal untrained men were studied during the intravenous infusion of a balanced amino acid mixture (approximately 0.15 g.kg-1.h-1 for 3 h) at rest and after a leg resistance exercise routine to test the influence of exercise on the regulation of muscle protein kinetics by hyperaminoacidemia. Leg muscle protein kinetics and transport of selected amino acids (alanine, phenylalanine, leucine, and lysine) were isotopically determined using a model based on arteriovenous blood samples and muscle biopsy. The intravenous amino acid infusion resulted in comparable increases in arterial amino acid concentrations at rest and after exercise, whereas leg blood flow was 64 +/- 5% greater after exercise than at rest. During hyperaminoacidemia, the increases in amino acid transport above basal were 30-100% greater after exercise than at rest. Increases in muscle protein synthesis were also greater after exercise than at rest (291 +/- 42% vs. 141 +/- 45%). Muscle protein breakdown was not significantly affected by hyperminoacidemia either at rest or after exercise. We conclude that the stimulatory effect of exogenous amino acids on muscle protein synthesis is enhanced by prior exercise, perhaps in part because of enhanced blood flow. Our results imply that protein intake immediately after exercise may be more anabolic than when ingested at some later time.

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Dexamethasone inhibits the stimulation of muscle protein synthesis and PHAS-I and p70 S6-kinase phosphorylation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.4.e570 ◽

2001 ◽

Vol 280 (4) ◽

pp. E570-E575 ◽

Cited By ~ 19

Author(s):

Wen Long ◽

Liping Wei ◽

Eugene J. Barrett

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Initiation Factor ◽

Glucose Disposal ◽

Acid Mixture ◽

S6 Kinase ◽

P70 S6 Kinase ◽

Amino Acid Infusion

Glucocorticoids inhibit protein synthesis in muscle. In contrast, insulin and amino acids exert anabolic actions that arise in part from their ability to phosphorylate ribosomal p70 S6-kinase (p70S6k) and eukaryotic initiation factor (eIF)4E binding protein (BP)1 (PHAS-I), proteins that regulate translation initiation. Whether glucocorticoids interfere with this action was examined by giving rats either dexamethasone (DEX, 300 μg · kg−1 · day−1, n = 10) or saline ( n = 10) for 5 days. We then measured the phosphorylation of PHAS-I and p70S6kin rectus muscle biopsies taken before and at the end of a 180-min infusion of either insulin (10 mU · min−1 · kg−1 euglycemic insulin clamp, n = 5 for both DEX- and saline-treated groups) or a balanced amino acid mixture ( n = 5 for each group also). Protein synthesis was also measured during the infusion period. The results were that DEX-treated rats had higher fasting insulin, slower glucose disposal, less lean body mass, and decreased protein synthetic rates during insulin or amino acid infusion ( P < 0.05 each). DEX did not affect basal PHAS-I or p70S6k phosphorylation but blocked insulin-stimulated phosphorylation of PHAS-I- and amino acid-stimulated phosphorylation of both PHAS-I and p70S6k ( P < 0.01, for each). DEX also increased muscle PHAS-I concentration. These effects can, in part, explain glucocorticoid-induced muscle wasting.

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Human muscle protein synthesis and breakdown during and after exercise

Journal of Applied Physiology ◽

10.1152/japplphysiol.91481.2008 ◽

2009 ◽

Vol 106 (6) ◽

pp. 2026-2039 ◽

Cited By ~ 148

Author(s):

Vinod Kumar ◽

Philip Atherton ◽

Kenneth Smith ◽

Michael J. Rennie

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Protein Turnover ◽

Acute Exercise ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Mitochondrial Protein ◽

Human Muscle ◽

Muscle Protein Turnover ◽

Amino Acid Availability

Skeletal muscle demonstrates extraordinary mutability in its responses to exercise of different modes, intensity, and duration, which must involve alterations of muscle protein turnover, both acutely and chronically. Here, we bring together information on the alterations in the rates of synthesis and degradation of human muscle protein by different types of exercise and the influences of nutrition, age, and sexual dimorphism. Where possible, we summarize the likely changes in activity of signaling proteins associated with control of protein turnover. Exercise of both the resistance and nonresistance types appears to depress muscle protein synthesis (MPS), whereas muscle protein breakdown (MPB) probably remains unchanged during exercise. However, both MPS and MPB are elevated after exercise in the fasted state, when net muscle protein balance remains negative. Positive net balance is achieved only when amino acid availability is increased, thereby raising MPS markedly. However, postexercise-increased amino acid availability is less important for inhibiting MPB than insulin, the secretion of which is stimulated most by glucose availability, without itself stimulating MPS. Exercise training appears to increase basal muscle protein turnover, with differential responses of the myofibrillar and mitochondrial protein fractions to acute exercise in the trained state. Aging reduces the responses of myofibrillar protein and anabolic signaling to resistance exercise. There appear to be few, if any, differences in the response of young women and young men to acute exercise, although there are indications that, in older women, the responses may be blunted more than in older men.

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Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids

Biochemical Journal ◽

10.1042/bj2540579 ◽

1988 ◽

Vol 254 (2) ◽

pp. 579-584 ◽

Cited By ~ 209

Author(s):

P J Garlick ◽

I Grant

Keyword(s):

Amino Acids ◽

Protein Synthesis ◽

Amino Acid ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Branched Chain Amino Acids ◽

Acid Infusion ◽

Amino Acid Infusion ◽

Branched Chain

Rates of muscle protein synthesis were measured in vivo in tissues of post-absorptive young rats that were given intravenous infusions of various combinations of insulin and amino acids. In the absence of amino acid infusion, there was a steady rise in muscle protein synthesis with plasma insulin concentration up to 158 mu units/ml, but when a complete amino acids mixtures was included maximal rates were obtained at 20 mu units/ml. The effect of the complete mixture could be reproduced by a mixture of essential amino acids or of branched-chain amino acids, but not by a non-essential mixture, alanine, methionine or glutamine. It is concluded that amino acids, particularly the branched-chain ones, increase the sensitivity of muscle protein synthesis to insulin.

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Combined effects of hyperaminoacidemia and oxandrolone on skeletal muscle protein synthesis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.278.2.e273 ◽

2000 ◽

Vol 278 (2) ◽

pp. E273-E279 ◽

Cited By ~ 21

Author(s):

Melinda Sheffield-Moore ◽

Robert R. Wolfe ◽

Dennis C. Gore ◽

Steven E. Wolf ◽

Dennis M. Ferrer ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acids ◽

Protein Synthesis ◽

Amino Acid ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Compartment Model ◽

Acid Mixture ◽

Skeletal Muscle Protein ◽

Amino Acid Infusion

We investigated whether the normal anabolic effects of acute hyperaminoacidemia were maintained after 5 days of oxandrolone (Oxandrin, Ox)-induced anabolism. Five healthy men [22 ± 3 (SD) yr] were studied before and after 5 days of oral Ox (15 mg/day). In each study, a 5-h basal period was followed by a 3-h primed-continuous infusion of a commercial amino acid mixture (10% Travasol). Stable isotopic data from blood and muscle sampling were analyzed using a three-compartment model to calculate muscle protein synthesis and breakdown. Model-derived muscle protein synthesis increased after amino acid infusion in both the control [basal control (BC) vs. control + amino acids (C+AA); P < 0.001] and Ox study [basal Ox (BOx) vs. Ox + amino acids (Ox+AA); P < 0.01], whereas protein breakdown was unchanged. Fractional synthetic rates of muscle protein increased 94% (BC vs. C+AA; P = 0.01) and 53% (BOx vs. Ox+AA; P < 0.01), respectively. We conclude that the normal anabolic effects of acute hyperaminoacidemia are maintained in skeletal muscle undergoing oxandrolone-induced anabolism.

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Latency, Duration and Dose Response Relationships of Amino Acid Effects on Human Muscle Protein Synthesis

Journal of Nutrition ◽

10.1093/jn/131.10.3225s ◽

2002 ◽

Vol 132 (10) ◽

pp. 3225S-3227S ◽

Cited By ~ 46

Author(s):

Michael J. Rennie ◽

Julien Bohé ◽

Robert R. Wolfe

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Dose Response ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Human Muscle ◽

Latency Duration

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The single-biopsy approach in determining protein synthesis in human slow-turning-over tissue: use of flood-primed, continuous infusion of amino acid tracers

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00084.2014 ◽

2014 ◽

Vol 306 (11) ◽

pp. E1330-E1339 ◽

Cited By ~ 17

Author(s):

Lars Holm ◽

Søren Reitelseder ◽

Kasper Dideriksen ◽

Rie H. Nielsen ◽

Jacob Bülow ◽

...

Keyword(s):

Amino Acids ◽

Protein Synthesis ◽

Amino Acid ◽

Continuous Infusion ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Synthesis Rate ◽

Protein Synthesis Rate ◽

Tissue Biopsy ◽

Infusion Protocol

Muscle protein synthesis (MPS) rate is determined conventionally by obtaining two or more tissue biopsies during a primed, continuous infusion of a stable isotopically labeled amino acid. The purpose of the present study was to test whether tracer priming given as a flooding dose, thereby securing an instantaneous labeling of the tissue pools of free tracee amino acids, followed by a continuous infusion of the same tracer to maintain tracer isotopic steady state, could be used to determine the MPS rate over a prolonged period of time by obtaining only a single tissue biopsy. We showed that the tracer from the flood prime appeared immediately in the muscle free pool of amino acids and that this abundance could be kept constant by a subsequent continuous infusion of the tracer. When using phenylalanine as tracer, the flood-primed, continuous infusion protocol does not stimulate the MPS rate per se. In conclusion, the flood-primed, continuous infusion protocol using phenylalanine as tracer can validly be used to measure the protein synthesis rate in human in vivo experiments by obtaining only a single tissue biopsy after a prolonged infusion period.

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Reducing plasma HIV RNA improves muscle amino acid metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00359.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. E278-E284 ◽

Cited By ~ 17

Author(s):

Kevin E. Yarasheski ◽

Samuel R. Smith ◽

William G. Powderly

Keyword(s):

Protein Synthesis ◽

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Synthesis Rate ◽

Protein Synthesis Rate ◽

Hiv Rna ◽

Muscle Protein Synthesis Rate

We reported (Yarasheski KE, Zachwieja JJ, Gischler J, Crowley J, Horgan MM, and Powderly WG. Am J Physiol Endocrinol Metab 275: E577–E583, 1998) that AIDS muscle wasting was associated with an inappropriately low rate of muscle protein synthesis and an elevated glutamine rate of appearance (Ra Gln). We hypothesized that high plasma HIV RNA caused dysregulation of muscle amino acid metabolism. We determined whether a reduction in HIV RNA (≥1 log) increased muscle protein synthesis rate and reduced Ra Gln and muscle proteasome activity in 10 men and 1 woman (22–57 yr, 60–108 kg, 17–33 kg muscle) with advanced HIV (CD4 = 0–311 cells/μl; HIV RNA = 10–375 × 103 copies/ml). We utilized stable isotope tracer methodologies ([13C]Leu and [15N]Gln) to measure the fractional rate of mixed muscle protein synthesis and plasma Ra Gln in these subjects before and 4 mo after initiating their first or a salvage antiretroviral therapy regimen. After treatment, median CD4 increased (98 vs. 139 cells/μl, P = 0.009) and median HIV RNA was reduced (155,828 vs. 100 copies/ml, P = 0.003). Mixed muscle protein synthesis rate increased (0.062 ± 0.005 vs. 0.078 ± 0.006%/h, P = 0.01), Ra Gln decreased (387 ± 33 vs. 323 ± 15 μmol·kg fat-free mass−1·h−1, P = 0.04), and muscle proteasome chymotrypsin-like catalytic activity was reduced 14% ( P = 0.03). Muscle mass was only modestly increased (1 kg, P = not significant). We estimated that, for each 10,000 copies/ml reduction in HIV RNA, ∼3 g of additional muscle protein are synthesized per day. These findings suggest that reducing HIV RNA increases muscle protein synthesis and reduces muscle proteolysis, but muscle protein synthesis relative to whole body protein synthesis rate is not restored to normal, so muscle mass is not substantially increased.

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