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Current Opinion in Clinical Nutrition & Metabolic Care:
doi: 10.1097/MCO.0b013e32834d19bc
PROTEIN, AMINO ACID METABOLISM AND THERAPY: Edited by Olav Rooyackers and John Brosnan

Regulation of muscle protein synthesis in humans

Phillips, Bethan E.; Hill, Derek S.; Atherton, Philip J.

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Division of Clinical Physiology, School of Graduate Entry Medicine and Health, University of Nottingham, Derby, UK

Correspondence to Dr Philip J. Atherton, Division of Clinical Physiology, School of Graduate Entry Medicine and Health, University of Nottingham, Derby Royal Hospital, Uttoxeter Road, Derby DE22 3DT, UK. Tel: +44 0 1332 724725; fax: +44 0 1332 724611; e-mail: philip.atherton@nottingham.ac.uk

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Abstract

Purpose of review: Investigations into the regulation of muscle protein synthesis (MPS) are a cornerstone of understanding the control of muscle mass. Rates of MPS are finely tuned according to levels of activity, nutrient availability and health status. For instance, rates of MPS are positively regulated by exercise and nutrition, and negatively regulated by inactivity (e.g. disuse), ageing (i.e. sarcopenia) and in muscle-wasting related diseases (e.g. cancer).

Recent findings: Skeletal muscles display a high degree of intrinsic regulation. Increases in MPS after exercise occur independently of the systemic milieu for example growth hormone/testosterone concentrations. In the absence of exercise, increases in MPS after feeding are of finite duration despite enduring precursor availability; that is muscles can sense they are ‘full’. Intriguingly, exercise delays this ‘muscle-full’ response to allow for building and repair. In contrast, muscle-wasting conditions exhibit a premature ‘muscle-full’ response to nutrition and exercise (i.e. anabolic resistance), which may cause atrophy. Observations of ‘dissociations’ between MPS and anabolic signalling pathways have cast doubt on how much we understand of the molecular regulation of human MPS.

Summary: Anabolic and anticatabolic interventions in health and disease should be aimed at manipulating the ‘muscle-full’ set point to maximize muscle maintenance/hypertrophy.

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INTRODUCTION

Muscle mass is maintained by a dynamic equilibrium in protein turnover in which net efflux of amino acids during fasting periods is offset by net influx (and incorporation into protein) during fed periods. Exercise, ageing and diseases associated with muscle wasting may modulate the capacity for muscles to incorporate available amino acids into protein which we propose represents the key aspect regulating hypertrophy and atrophy.

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REGULATION OF MUSCLE PROTEIN SYNTHESIS BY NUTRIENTS: NEW FINDINGS

The anabolic effects of feeding are driven through two principal mechanisms: first, fractional synthesis rates of muscle proteins increase approximately 300% [1▪▪] and second, muscle protein breakdown (MPB) rates are depressed approximately 50% [2]. As the magnitude of change in muscle protein synthesis (MPS) is greater than those of MPB, increases in MPS are the main driver of anabolic responses to feeding. Work over the past 20 years has established that the anabolic effects of feeding could not occur without ingestion of foodstuffs sufficient in essential amino acids (EAA; [3]) and more recently that additional macronutrients have no additive anabolic effects; that is addition of carbohydrate to protein neither enhances MPS nor attenuates MPB [4▪▪]. Of course, teleologically, the anabolic effects of EAA must be short-lived otherwise one could achieve hypertrophy through overfeeding (forsaking adaptive increases in MPB). Indeed, recent work by Atherton et al. [1▪▪] has confirmed this premise: young men provided an oral bolus of 48 g whey protein demonstrated 300% increases in MPS between 45–90 min which rapidly returned to baseline thereafter. Curiously, declines in MPS occurred despite sustained plasma and muscle amino acids availability suggesting an innate ‘muscle-full’ set point rather than MPS being driven by plasma/intracellular amino acids bioavailability per se.

What about the mechanism of increased MPS in response to EAA? Confirmation of a role for mammalian target of rapamycin complex 1 (mTORc1) signalling was recently provided in a study in which administration of rapamycin (a specific inhibitor of mTORc1) blocked increases in MPS and mTORc1 signalling after oral EAA in humans [5▪▪]. In agreement with this, Atherton et al. [1▪▪] reported that after feeding 48 g whey protein, rising MPS rates were matched closely with mTORc1 substrate phosphorylation. It would then seem a straightforward assertion that mTORc1 signalling controls the anabolic effects of EAA, albeit with a caveat. In the latter study, the authors found that declines in MPS to baseline 90 min after feeding (‘muscle-full’) occurred despite continued upregulation of mTORc1 signalling, thus revealing a ‘dissociation’ between mTORc1 and MPS [6]. Nonetheless, whether this is a true dissociation or an artefact of using single phosphorylation sites as a proxy for kinase activity remains to be defined. Recent work has also provided new evidence that amino acids transporters might serve as more sophisticated import mechanisms than first thought. For instance, it was shown that the anabolic effects of leucine require glutamine efflux via sodium-coupled neutral amino-acid transporter member 2 (SNAT2) so the system-L amino acid transporter 1 (LAT1) heteroexchange system can import leucine [7]. Importantly, these transporters have been demonstrated to be acutely regulated by oral EAA in humans, with Rasmussen's group reporting increases in mRNA and protein for LAT1 and SNAT2 [8▪▪]. These findings suggest that EAA are downstream as well as upstream of amino acids transporters.

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REGULATION OF MUSCLE PROTEIN SYNTHESIS BY EXERCISE: NEW FINDINGS

Increasing muscle mass is the aim of bodybuilders and recreational weightlifters alike, but also represents the foremost intervention in offsetting declines in muscle mass in ageing and other muscle-wasting conditions. In terms of understanding the mechanisms of muscle hypertrophy an emerging theme is the intrinsic capacity of muscle to adapt to exercise. For example, in an elegantly designed study, West et al. [9▪▪] manipulated endogenous concentrations of ‘anabolic hormones’ [growth hormone (GH) and testosterone] through varying muscle recruitment volume thereby creating a ‘high’ hormone and ‘low’ hormone environment. Intriguingly, systemic concentrations of GH and testosterone did not impact either acute responses to exercise in terms of MPS or adaptive responses to resistance exercise training in terms of muscle hypertrophy [10▪▪]. In agreement with a questionable role for these hormones on human MPS, 14-day recombinant GH administration which increased serum GH, insulin-like growth factor (IGF-1) and IGF-1 mRNA expression in muscle did not affect MPS [11▪]. Thus, contrary to widespread belief, ostensibly anabolic hormones do not drive (i.e. are permissive at best) MPS or loading-induced adaptation in humans, which must instead be controlled by intrinsic autocrine/paracrine factors and mechanotransduction processes.

Not only must muscle cells have an intrinsic signal to increase MPS, but also selectivity over which proteins are to be synthesized, that is resistance training increases myofiber size, whereas endurance training enhances fatigue resistance. Measuring MPS in distinct muscle fractions (sarcoplasmic, collagen, myofibrillar, mitochondria) could prove valuable in predicting such chronic alterations in muscle phenotype. For example, Wilkinson et al. [12] reported that, whereas endurance trained individuals specifically upregulated mitochondrial protein synthesis after exercise, those resistance trained upregulated myofibrillar protein synthesis. In addition, Moore et al. [13] reported that resistance type exercise induced sustained increases in myofibrillar but not sarcoplasmic MPS. Together, these results support the concept that myofibrillar protein accretion is quantitatively more important for muscle hypertrophy [12]. Nonetheless, we know nothing of the intracellular signals regulating these fraction-specific adaptations which were found to be similar irrespective of fraction-specific regulation of MPS; more work is needed to address this [12].

How can we maximize anabolic responses to exercise? Optimizing patterns of loading and nutrition represent a major area of study. For example, recent findings have cast new light on the role that the intensity of exercise has in determining MPS responses to exercise. For instance, work from Kumar et al. [14] has shown a sigmoidal dose response to resistance exercise such that MPS is greatest at exercise intensities greater than 60% 1 repetition maximum (1-RM); even wherein repetition number is increased at lower intensities (20–40%) to balance workloads. These findings support the notion that exercising above 60% 1-RM represents an anabolic ‘ceiling’. Interestingly, the intensity of exercise to elicit a robust increase in MPS can be reduced drastically (20% 1-RM) when combined with blood flow restriction (i.e. vascular occlusion [15▪]) suggesting that high-intensity exercise is not a prerequisite for exercise-induced increases in MPS. Indeed, increasing the volume of work at a low intensity (30% to failure) was shown to be more effective than low-volume, high-intensity exercise (90% to failure) [16▪] in terms of amplitude/duration of MPS after exercise. Although the work done was much greater in the 30% group, these findings are important as they suggest that high-intensity exercise per se is not a prerequisite for maximizing MPS after exercise and factors such as fibre recruitment or muscle perfusion may also be important. Nonetheless, how manipulating these parameters would translate into training adaptation remains to be fully defined.

It is well established that nutrient sufficiency represents a necessary component of muscle remodelling and hypertrophy [17] and that EAA potentiates acute anabolic responses to exercise. However, recent work has provided new information surrounding the synergistic anabolic effects of exercise and nutrients: Moore et al.[18▪▪] reported that the phosphorylation of mTORc1 and mitogen-activated protein kinase related proteins were shown to be greater with the combination of exercise and feeding than feeding alone which may explain additive effects on MPS. Although the question over optimal timing of nutrient intake has been a hotly researched topic, recent observations of Burd et al. [19▪▪] have highlighted good reason to question the importance of timing. This is because even 24 h after a single bout of unilateral resistance exercise, provision of EAA caused a much greater increase in MPS in the exercised than rest leg which suggests that the additive effects of exercise on MPS response to EAA are long-lived (i.e. there is a delaying of the ‘muscle-full’ signal; see Fig. 1). Therefore, it is speculated that consuming adequate dietary EAA intake is likely to be more important than timing per se.

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Nonetheless, recent work has highlighted that even the most optimal of feeding and exercise strategies may not elicit substantial effects in all individuals. In a recent study by Davidsen et al. [20▪▪], a fully supervised resistance exercise training program to younger adults elicited strikingly heterogeneous mass and strength gains, a continuum from which the authors categorized the top 20% ‘high’ and bottom 20% ‘low’ responders. Profiling of miRNA in these distinct responders yielded four miRNA species which were associated with training responsiveness: for example in ‘low responders’ miR-378, 29a and 26a were downregulated, whereas miR-451 was upregulated. These findings suggest that these miRNAs may have a role in determining adaptive heterogeneity. In another study, Mayhew et al.[21▪] determined that increased concentrations of eukaryotic initiation factor 2B epsilon (eIF2Bε) protein after a single exercise bout was directly associated with the degree of hypertrophy after resistance exercise training, and that in-vitro overexpression of eIF2Bε lead to muscle hypertrophy; thus upregulation of eIF2Bε may partly underlie adaptive capacity. Clearly then, using biological variability represents a powerful approach in terms of both bioprediction and gaining mechanistic insight in human studies and more work is needed to link measures such as noncoding RNA, mRNA, intracellular proteins and MPS in humans. For instance, it could be speculated that heterogeneity in the muscle-full set point may underlie adaptive capacity.

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REGULATION OF MUSCLE PROTEIN SYNTHESIS IN CATABOLIC CONDITIONS: THE CONCEPT OF ANABOLIC RESISTANCE

Causes of muscle atrophy may be broadly separated into sarcopenia, disuse, and wasting-associated diseases. Although it has long been known that declines in postabsorptive MPS and/or increases in MPB (depending upon the driving cause) are a catalyst for muscle atrophy, recent work has uncovered a new layer of dysregulation termed anabolic resistance that seems to transcend the cause of atrophy. In a nutshell, anabolic resistance is a deficit in the capacity to mount anabolic responses to activity and nutrients [22,23]; the key influences of muscle maintenance. It is postulated by the authors that anabolic resistance represents a perpetual ‘premature muscle-full state’ (see Fig. 1) that underlies and/or exacerbates atrophy and perhaps contributes to maladaptation to exercise (i.e. in ageing).

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ANABOLIC RESISTANCE TO FEEDING IN AGEING MUSCLES

Although sarcopenia must involve an imbalance between MPS and MPB, rates of MPS and MPB during postabsorptive periods are unchanged with age. As such, other mechanisms have been sought, one of which being anabolic resistance. In support of this concept, Cuthbertson et al. [24] compared responses in MPS to oral EAA over a wide availability (2.5–40 g) and found that above 5 g EAA, older men exhibited smaller increases in MPS to those seen in young people. In contrast, others have also reported anabolic resistance but only at lower doses of EAA [25] and Symons et al. [26] found that administration of 113 g of lean beef (∼30 g protein) raised MPS by approximately 50% in both young and old healthy patients. Similarly, Chevalier et al., [27▪] found no blunting in the anabolic response under hyperglycaemic, hyperinsulinaemic, hyperaminoacidaemic conditions in which blood concentrations of insulin, total amino acids and glucose were maintained at approximately 300–400 pmol l−1, 3300 μmol l−1 and 8 mmol l−1, respectively. Although these findings support the notion that overcoming anabolic resistance is simply a matter of increasing total amino acid load [24]; they remain at odds to reports of anabolic resistance after consumption of 20–40 g EAA [24].

Consequently, perhaps it is the ‘quality’ (i.e. specific amino acids content form) rather than quantity of amino acids that is important for overcoming anabolic resistance. Pennings et al.[28▪] used intrinsically stable isotopically labelled proteins to compare acute anabolic responses of older men to casein, casein hydrolysate and whey protein. Protein synthesis rates were significantly higher following whey ingestion (0.15% h−1) than casein (0.08% h−1) or casein hydrolysate (0.10% h−1); a result which the authors explained as being due to the faster absorption rates and a higher peak plasma concentration of leucine. Intriguingly, the Phillips lab recently demonstrated that a large single bolus of protein was more effective in stimulating MPS than the sum of quantitatively equivalent small boluses in younger men [29▪]. Together, these data support the concept that rapid exposure of muscle to amino acids and/or peak leucine concentration may be important in determining anabolic sensitivity (Note: free-EAA would be absorbed more slowly than proteins). Finally, research concerning overcoming anabolic resistance may not be restricted to amino acids composition/quantity as other novel interventions have proved efficacious. For example, 8-week supplementation of omega-3 fish oils ameliorated anabolic resistance in elderly men [30▪]. Thus, although consensus on whether, and how, anabolic resistance may be overcome remains ill defined, initial research is promising.

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ANABOLIC RESISTANCE TO EXERCISE IN AGEING MUSCLES

As is the case with feeding, there is also evidence for anabolic resistance to exercise in ageing. For instance, 1–2 h after exercise, Kumar et al.,[14] reported that MPS responses were blunted in the elderly over a range of intensities of resistance exercise performed in the postabsorptive state (20–90% 1-RM). These findings were further corroborated by Fry et al.[31▪▪] who showed aging impairs contraction-induced human skeletal muscle mTORc1 signalling and protein synthesis when sampling up to 24 h after exercise. Collectively, these data may explain age-related reductions in trainability (i.e. muscle hypertrophy) with resistance exercise training [32▪]. Moreover, the findings of anabolic resistance are not restricted to resistance type exercise: Durham et al.,[33▪] also reported age-related declines in MPS responses to endurance type exercise (i.e. walking) in the fed state. Therefore, it is speculated that anabolic insensitivity even to mild, habitual activity may exacerbate the catabolic effects of sedentarism associated with ageing. Nonetheless, as with feeding, conflicting data cast doubt over the existence of anabolic resistance to exercise. For example, Symons et al.[34▪] found that when a bout of resistance exercise was combined with a high quality protein meal there was no difference in MPS responses between young and older individuals and Drummond et al.[35] reported that the ‘cumulative’ anabolic response to resistance exercise and EAA is similar but the response is simply delayed with ageing. Nonetheless, we contend that shorter-duration exercise studies (unlike for feeding alone [1▪▪]) cannot capture the complete long-term anabolic effects of exercise [19▪▪]. As such, the study by Fry et al. [31▪▪] in which anabolic resistance was confirmed over an extended recovery (3, 8 and 24 h after exercise) encompassing fasted and fed periods, is more likely to identify small but important differences which otherwise could be masked under short-study formats and with heterogeneity in small sample sizes.

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ANABOLIC RESISTANCE TO NUTRIENTS AND EXERCISE: BEYOND AGEING?

New work is beginning to show that anabolic resistance transcends age-related muscle wasting. Disuse atrophy is where muscles waste purely due to withdrawal of neural/mechano-input and (unlike ageing) is associated with declines in postabsorptive MPS rates, but also a very clear anabolic resistance to EAA [36]. Can we assess the impact of anabolic resistance on muscle atrophy in disuse? Yes! Consider the following: normal turnover is 0.05% h−1 or 1.2% d−1 in which MPS and MPB are equal and opposite. As MPS increases approximately three-fold for 1.5 h and approximately 5 h per day is spent in fed periods [1▪▪], based on conservative assumptions from previous findings in disuse in which MPS was suppressed approximately 50% in both postabsorptive and fed periods then diurnal protein accretion would be: [0.025 × 19 (fasted)] + [0.025 × 1.5 × 5 (fed)] = 0.66% day−1. Thus, if MPB remained constant then muscle would be lost at a rate of: 1.2−0.66 = 0.54% day−1, a figure entirely consistent with that measured (∼0.6% day−1) over the first 30 days of immobilization [37]. Therefore, suppressions in postabsorptive MPS coupled to anabolic resistance are sufficient to explain muscle loss in disuse (Note: without the need for increases in MPB). Although to date few other muscle-wasting conditions have been investigated, there is emerging evidence that anabolic resistance may be a common feature. For example, Tuvdendorj et al.[38▪▪] recently showed that skeletal muscles of paediatric burn patients are unresponsive to EAA and Deutz et al.[39▪▪] showed the same in cancer patients. Finally, evidence is mounting that the ability to inhibit MPB postprandially is also diminished [2,40▪]. Thus, if present, the inability to reduce MPB after feeding would exacerbate the wasting due to anabolic resistance in MPS.

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CONCLUSION

Human MPS is intrinsically regulated. Growth is achieved by delaying the ‘muscle-full’ signal whereas approaches to minimize muscle atrophy may be achieved by doing the same that is ameliorating anabolic resistance (Fig. 1).

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Acknowledgements

None.

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Conflicts of interest

P.J. Atherton is supported by a Research Councils UK fellowship and Ajinomoto Inc. D.S. Hill has a PhD studentship supported by an NIH-NIAMS grant (AR-054342) and the University of Nottingham and B.E. Phillips is a BBSRC funded research associate (BB/C516779/1).

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 94–95).

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References

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Keywords:

anabolic resistance; mTOR signalling; protein synthesis; skeletal muscle

© 2012 Lippincott Williams & Wilkins, Inc.

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