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Human Muscle Protein Synthesis After Physical Activity and Feeding

Miller, Benjamin F.

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Exercise and Sport Sciences Reviews: April 2007 - Volume 35 - Issue 2 - p 50-55
doi: 10.1097/jes.0b013e31803eac78
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INTRODUCTION

An important development in skeletal muscle protein metabolism has been the observed effect of postexercise nutrition on skeletal muscle protein synthesis. Some have viewed this as an additive response of physical activity and nutrition. Although this view is appropriate, a further refinement is that physical activity has triggered an adaptive response to which the nutrition provides the necessary building blocks for an optimal response (Fig. 1). In other words, nutrition is necessary to take advantage of an adaptive environment created by exercise. To understand this reasoning, it is necessary to take a broader view regarding the roles of nutrition and physical activity in skeletal muscle plasticity, namely storage and adaptation. In this review, storage is defined as depositing a macronutrient in a tissue for future use, whereas adaptation refers to becoming better suited for one's environment.

Figure 1
Figure 1:
Food containing essential amino acids (EAA) signal that a meal has been consumed, and the resulting increase in systemic protein synthesis functions to store amino acids (AA) to sustain the AA pool in times of protein shortage(dotted lines). Mechanical (or energetic) stimulation signal that the muscle has been stressed. The local increase in protein synthesis lasts on the order of days and is not maximal (dashed lines) unless AA and energy are provided (solid lines).

Because a broad framework is being proposed, discussions of cellular signaling pathways will purposely be avoided. In fact, it is the hope that the point of view expressed here will be used to add perspective to data from cellular studies (i.e., provide contextual framework to interpret outcomes). Independently, the pieces of the hypothesis are not new; however, when considered together, they provide a novel perspective.

NUTRITION

The "thrifty gene" hypothesis posits that we evolved metabolically thrifty genes that hasten the storage of nutrients when available so that the individual will survive subsequent periods of food scarcity (14). The evolution of the thrifty genotype is hypothesized to have occurred around 50,000 to 10,000 BC when feast and famine were the norm. Therefore, those who could efficiently store nutrients during a time of food abundance were better off during subsequent periods of food scarcity. The "thrifty gene" hypothesis was conceived to explain how diabetes has been conserved when its detrimental effects should be selected against. Because much of the focus of the "thrifty gene" hypothesis has been on issues of fat and carbohydrate storage and the subsequent dysfunction of energy metabolism, the third macronutrient, protein, has been largely overlooked.

Just as adipose is the storage depot of excess free fatty acids and muscle and liver glycogen are the storage site of glucose, skeletal muscle can be viewed as the storage depot of amino acids (AA). As mentioned by Wolfe (24), skeletal muscle protein is the only AA reserve in the body capable of significant losses without compromising the ability to sustain life. In the fasted state, skeletal muscle protein breakdown increases to sustain the free AA pool. Conversely, when fed, AA stimulate muscle protein synthesis to maintain AA stores during subsequent fasts. Therefore, skeletal muscle protein is a dynamic AA reservoir sensitive to the fed and fasted states. The success of this system can partially be attributed to the large quantity, 7 kg in a 70-kg man (23), of skeletal muscle protein.

Much of the insight into the storage phenomena has been provided by studies conducted by M.J. Rennie and his colleagues. With a sophisticated methodological design, Smith et al. (19) stumbled upon an important physiological phenomenon while investigating the continuous versus flooding-dose technique for the measurement of skeletal muscle protein synthesis. The authors observed that a flooding dose of essential amino acids (EAA) stimulated the fractional synthesis rates (FSR) of skeletal muscle protein when simultaneously measured by the continuous infusion technique (Fig. 2). However, when nonessential AA (NEAA) were used as a flood, FSR was not increased. The stimulation of muscle protein synthesis by EAA is an interesting display of human design. Because EAA by definition can only come from the diet, the increased concentration of EAA indicates that a meal has been consumed. The signaling of a consumed meal would not work with NEAA because the concentrations of NEAA can change in the absence of a meal through transamination.

Figure 2
Figure 2:
Essential amino acid (EAA) signal that a meal has been consumed because EAA must come from an exogenous source. The presented data (hatched bars, preflood; solid bars, postflood) demonstrate that only flooding doses of EAA, but not NEAA, stimulate muscle protein synthesis rates when measured by a [13C]leucine constant infusion (postflood value is significantly different from preflood value (P < 0.05); NS indicates not significant). (Phe) indicates phenylalanine. (Thr) indicates threonine. (Arg) indicates arginine. (Gly) indicates glycine. (Ser) indicates serine. (Reprinted from Smith, K., N. Reynolds, S. Downie, A. Patel, and M.J. Rennie. Effects of flooding amino acids on incorporation of labeled amino acids into human muscle protein. Am. J. Physiol. 275:E73-E78, 1998. Copyright © 1998 The American Physiological Society. Used with permission.)

The dynamic exchange of AA between the free AA pool and skeletal muscle is rapid and, in adequately fed individuals, maintains skeletal muscle mass over days and weeks. In the postprandial period, EAA stimulate an increase in skeletal muscle protein synthesis so that a net positive AA balance results. During the transition from a postprandial to a postabsorptive period, net balance shifts from a positive to a negative balance. In a 24-h period, net balance will usually equal zero (17). Therefore, feeding helps modulate short-term variations in the AA pool as opposed to long-term phenotypic changes. Finally, it is also important to note that after feeding, skeletal muscle in diverse anatomical locations shows increases in protein FSR by similar amounts (4,12), indicating that this stimulation is a systemic rather than a muscle-specific effect.

To summarize, EAA signal that a meal has been consumed; therefore, AA should be deposited in the skeletal muscle protein reservoir. The feeding effect is relatively transient and systemic and helps to sustain the body's AA pool during the intervening period between meals (Fig. 1).

PHYSICAL ACTIVITY

The capacity for change and adaptation in skeletal muscle has been termed plasticity. Skeletal muscle has an enormous capacity to adapt to stress. Although the adaptive response can be addressed at many different levels, the common process remains the same; a system is stressed, the stressor is sensed, the sensing triggers a response, and the response is designed to bring about change to minimize the perturbation from homeostasis caused by the original stress.

Physical activity introduces a variety of stressors from energetic challenges to mechanical overload. The search for the appropriate sensors, such as adenosine monophosphate-activated protein kinase or integrins, and their method of action will undoubtedly keep scientists busy for some time. However, the response is something that is relatively (at least compared with the stressor and sensor) well investigated. For instance, resistance exercise stimulates mechanoreceptors that trigger a rapid increase in transcription of new messenger RNA (mRNA) and the translation of already present mRNA. However, also important is the increase in the transcription and translation of proteins such as growth factors that signal a prolonged (up to 72 h) anabolic response to exercise. These responses create an adaptive potential; however, like any metabolic reaction, the proper substrate must be provided.

The use of stable isotopes has increased understanding of the adapted response of muscle to mechanical loading. After a bout of heavy resistance training, mixed muscle protein synthesis is increased for up to 48 h (15). Similarly, after a bout of exercise that is best described as "strenuous," we reported increases in myofibrillar protein synthesis that peaked at 24 h and remained elevated at 72 h (10). Interestingly, over the same period after exercise, the muscle extracellular matrix and tendon increased protein synthesis in a similar pattern (10). Our interpretation was that a mechanical stimulus, in the one-legged kicking model, stimulated a coordinated adaptive response to make the musculotendinous unit more able to handle subsequent loading. This coordinated response, of course, is the well-known phenomenon of specificity. The important point here is that the response of protein synthesis to physical activity is adaptive and relatively long term as opposed to a transient storage phenomenon after feeding. Finally, another important distinction regarding specificity is that, as opposed to the systemic response of feeding on all skeletal muscle, physical activity only stimulates a response in the stimulated muscle; hence, the response is a local rather than a systemic one (Fig. 2).

ENERGETICALLY EXPENSIVE

When considering the process of protein synthesis, the importance of AA as building blocks of protein is appreciated. However, less appreciated is the role of energy in the protein synthetic process, which may be as important as protein intake for maintaining lean body mass (22). Muscle protein synthesis is an energetically expensive process. In fact, in the basal state, isolated cells use more adenosine triphosphate (ATP) for muscle protein synthesis than any other cellular process (18) and can account for 20% of resting energy expenditure. For every peptide bond, four ATP are needed so that for an average 300 AA protein, 1200 ATP are required (18). Second, AA are a small but significant energy source, especially when other energy sources are in short supply. Although current protein recommendations are based on absolute quantities (g·kg−1 per body weight) and were made assuming energy balance, protein requirements should not be considered in the absence of energy status. The dependence of nitrogen status on energy balance is not a new concept (6,22); however, it is one that is often overlooked when considering protein responses to feeding and physical activity.

PHYSICAL ACTIVITY AND NUTRITION

It is now apparent that timing protein nutrition after a bout of exercise increases skeletal muscle protein synthesis and net balance to a greater extent than exercise in the fasted state (21). To many, the greater increase has been viewed as an additive response of exercise and nutrition; however, it is likely that the physical activity triggers an adaptive response, and the nutrition provides the macronutrient substrates for taking advantage of the stimulus (Fig. 1). Comparison of the roles of protein synthesis and breakdown on protein balance helps to clarify these roles.

For comparison purposes, the condition of 12-hr fasted values will be used as a baseline. Measurements of protein synthesis and breakdown after a 12-hr fast indicate that breakdown exceeds synthesis, so net protein balance is negative (see (16)). If one is fed or receives an infusion of mixed AA after a fasted period, protein synthesis increases, whereas protein breakdown remains the same or decreases slightly. This response is indicative of a storage phenomenon in which synthesis increases without an increase in breakdown. In the period after exercise without nutrient provision, protein synthesis and protein breakdown are increased compared with the 12-hr fasted reference values, indicating that there is a stimulus (exercise) and remodeling (increase in synthesis and breakdown) response, although net balance does not improve to a positive balance. When there is an exercise stimulus with postexercise AA feeding, protein synthesis increases more than that after exercise or AA feeding alone, and protein breakdown remains similar to exercise without feeding. Because there is an increase in protein synthesis above the rate observed after exercise but not AA provision, it is apparent that the provision of AA enhances protein synthesis. In addition, although protein breakdown is increased, it does not increase more than the fasted exercise response, consistent with an optimization.

In summary, the increase in protein synthesis after feeding is a transient storage phenomenon, whereas physical exercise stimulates a longer-term adaptive response. Providing nutrition after physical activity takes advantage of the anabolic signaling pathways that physical activity has initiated by providing AA building blocks and energy for protein synthesis.

HOW DOES THIS ENHANCE OUR UNDERSTANDING OF SKELETAL MUSCLE PROTEIN METABOLISM?

To answer this question, recent studies that investigated both myofibrillar and collagen responses to strenuous exercise are useful. It has been reported that, as opposed to myofibrillar protein synthesis, intramuscular connective tissue is not responsive to nutrition (10,12). At first appearance, this was confusing because we had previously speculated that muscle collagen and noncollagen proteins adapt in a coordinated manner (10) (Fig. 3); however, in the context of the proposed framework, the results make sense. The experiments that concluded that collagen was not sensitive to nutrition measured myofibrillar and collagen protein synthesis rates at rest before and after AA feeding. In both studies, myofibrillar protein synthesis increased with provision of AA, whereas collagen protein synthesis did not. As stated, feeding stimulates a transient storage phenomenon in the skeletal muscle protein reservoir. However, muscle collagen is not a reservoir of AA because it cannot "afford" changes in protein content in the same manner that contractile and other muscle proteins can. Therefore, it is not surprising that skeletal muscle collagen synthesis did not increase.

Figure 3
Figure 3:
The figure demonstrates the coordinated increases in the rates of protein synthesis of myofibrillar and muscle collagen protein after exercise. The experiment was done in the fed state at each time point. Although muscle collagen does not increase the rate of protein synthesis at rest after feeding, it is hypothesized that the increase in the rate of collagen protein synthesis in the figure is larger than that if the measurements were done in the fasted state. (FSR) indicates fractional synthesis rate. (Reprinted from Miller, B.F., J.L. Olesen, M. Hansen, S. Dossing, R.M. Crameri, R.J. Welling, H. Langberg, A. Flyvbjerg, M. Kjaer, J.A. Babraj, K. Smith, and M.J. Rennie. Coordinated collagen and muscle protein synthesis in human patella tendon and quadriceps muscle after exercise.J. Physiol. 567:1021-1033, 2005. Copyright © 2005. Used with permission.)

Four studies have examined collagen protein synthesis in the muscle after an acute bout of exercise (5,9,10,13). All four of these studies were performed in the fed state; in all cases, muscle collagen protein synthesis increased in a magnitude similar to muscle contractile protein synthesis. It would be interesting to examine the protein synthetic response of muscle collagen after exercise in the fasted state. Based on the framework proposed here, one would hypothesize that, although muscle collagen protein FSR does not change with feeding at rest, it would increase to a greater extent with feeding after a bout of exercise compared with exercise without feeding. In the rested state, provision of AA stimulates storage as skeletal muscle protein but not collagen; after exercise, it is providing the building blocks to take advantage of an adaptive response in both tissues.

PARALLELS WITH GLYCOGEN METABOLISM

Glycogen supercompensation refers to the phenomenon in which there is a large increase in glycogen concentration, above the well-fed sedentary state, when glycogen-depleting exercise is followed by carbohydrate feeding. Feeding or even overfeeding carbohydrate in the basal state will increase glycogen concentrations until "full." However, to supercompensate glycogen stores, a glycogen-depleting bout of exercise needs to precede carbohydrate feeding. In addition, supercompensation will only occur in the muscles that received the exercise stimulus (3). If there is a glycogen-depleting bout of exercise but no carbohydrate feeding, the muscle will maintain a capacity to supercompensate glycogen until the actual substrate (glucose) is provided (8). Finally, glycogen storage costs two ATP per glucose stored and requires energy provision above the stored amount. Thus, in muscle, feeding with both AA and glucose stimulates storage as protein or glycogen, respectively. However, an exercise stimulus triggers adaptation, with provision of building blocks and energy necessary for optimization.

ROLE OF INSULIN

The role of insulin in the regulation of protein turnover is one that continues to be controversial. It is usually accepted that insulin inhibits muscle protein breakdown; however, insulin's role in muscle protein synthesis is less clear. In resting subjects, the importance of insulin, AA, and energy for increased protein storage can be determined if each factor is independently eliminated (Table 1). At low concentrations of insulin (5-7 mU·L−1) and adequate glucose (5.4 mM), a systemic AA infusion stimulates muscle protein synthesis (20). Recently, Bell et al. (2) demonstrated that systemic infusion of insulin and energy, without infusion of AA, did not increase muscle protein synthesis. In the same study, local infusion of insulin, to maintain AA concentration, with low energy, stimulated muscle protein synthesis. These results demonstrate that AA are the primary factor driving an increase in muscle protein synthesis; although insulin and energy (glucose) can modulate the response, they alone are not sufficient to support a full synthetic response. A recent study by Fujita et al. (7) confirms this in that hyperinsulinemia only stimulates an increase in muscle protein synthesis when accompanied by increased AA delivery. In reality, a mixed meal, the kind people normally consume, will contain all three dietary macronutrients for optimal protein storage. Finally, is insulin necessary for the anabolic response after exercise? Again, consider the 12-hr fasted period as a reference. When there is an exercise stimulus with no postexercise feeding, both protein synthesis and breakdown increase. Because a large change in insulin in the fasted state after exercise is not expected, it is apparent that protein synthesis can increase without an increase in insulin concentration. In fact, the robust increase in muscle protein synthesis seen postexercise in the fasted state, when insulin is quite low (i.e., <8-10 mU·L−1), lends some support to the concept that insulin does not have to be elevated for a rise in muscle protein synthesis to occur. However, as discussed above, AA, energy, and perhaps higher insulin concentrations would maximize the adaptive response.

TABLE 1
TABLE 1:
Muscle protein synthetic responses with variation in insulin, AA, and energy in human subjects.

OTHER CHALLENGES AND CONCLUSIONS

The present discussion has focused on the responses of skeletal muscle protein metabolism. However, the proposed theory might be applicable to other tissue such as bone because it has been reported that the bone is responsive to nutrition in the rested state (1). In the context of the proposed hypothesis, the possibility that the bone is also an AA reservoir or that the bone is chronically adapting would even need to be considered. The idea that the bone is an AA reservoir is possible, given its role as a reservoir of mineral salts, and that chronic energy deficit results in decreased bone mass (11). Secondly, the observation that transamination and AA oxidation increase after feeding has led some to conclude that there is not really a true "storage site" for protein. Again, parallels must be drawn to glucose metabolism in that, although glucose storage increases after feeding, there is also an increase in oxidation and storage as fat in some conditions. Therefore, the possibility that, over short-term periods, there is a maximal storage of protein must be considered.

The purpose of this review was to provide a broad framework to which mechanistic studies can be put into context. As proposed, the adaptive response to exercise is ultimately dependent on the provision of AA building blocks for protein synthesis and carbohydrate, or possibly lipid, for an energetically expensive process. Therefore, studies that have examined factors such as increased mRNA or the up-regulation of translation initiation factors in skeletal muscle in response to exercise are indicative of adaptive potentials and not outcomes. This viewpoint fits well with the growing opinion that mechanistic studies in skeletal muscle should be combined with actual determination of protein synthesis. However, there is a need to develop new methods sensitive enough to measure protein-specific synthesis rates. Although many have distinguished between rates of myofibrillar (including myosin heavy chain and actin), sarcoplasmic, and even collagen protein synthesis, it would be insightful to address more specific protein responses. For instance, are all proteins within the myofiber equally susceptible to feeding-induced changes in content, and are there fiber type-specific responses to different exercise stimuli and/or feeding?

Acknowledgment

The author thanks Stuart M. Phillips for the feedback on the manuscript and Barry Braun for the encouragement to write it.

References

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Keywords:

protein turnover; exercise; nutrition; muscle collagen; anabolic; metabolism

© 2007 American College of Sports Medicine