Understanding the effects of nutrition and post-exercise nutrition on skeletal muscle protein turnover

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Skeletal muscle is the largest organ of the human body and plays a pivotal role in whole-body homeostasis through the maintenance of physical and metabolic health. Establishing strategies aimed at increasing the amount, and minimizing loss, of muscle mass are of utmost importance. Muscle mass is primarily dictated by the meal-to-meal fluctuations in muscle protein synthesis (MPS) and muscle protein breakdown (MPB), each of which can be quantified through the use of stable isotopically labeled tracers. Importantly, both MPS and MPB can be influenced by external factors such as nutritional manipulation, specifically protein ingestion, and changes in loading via exercise. To date, research involving stable isotopic tracers has focused on determining the optimal dose, timing surrounding bouts of exercise, distribution, and composition of protein to maximally stimulate MPS and inhibit MPB, both at rest and following exercise. In this review, we focus on the use of these stable isotopically-labeled tracers to unravel the intricacies of skeletal muscle protein turnover in response to specific nutritional interventions.

1. Introduction

Skeletal muscle is a remarkably plastic tissue that can change its phenotype in response to changes in loading demands. Skeletal muscle also plays an integral role in whole-body metabolism and homeostasis. The rate of muscle protein turnover is dependent on the balance between two opposing, ongoing, but interrelated kinetic processes: muscle protein synthesis (MPS) and muscle protein breakdown (MPB). This continuous turnover of muscle proteins results in efficient repair and renewal of damaged (whether mechanically, via oxidation, misfolding, nitrosylation, or otherwise) proteins and underpins the plasticity of skeletal muscle in response to contractile and nutritional perturbations [1]. In the postabsorptive state, MPB exceeds MPS and muscle proteins are catabolized to supply amino acids (AA) back into the free pool, but most of which are recycled and reused. However, some AA is lost from muscle, mostly as alanine and glutamine (nitrogen carriers) for glucose production via gluconeogenesis, or as a fuel for enterocytes. When MPB exceeds MPS, the net catabolism of skeletal muscle or a negative net protein balance (NPBAL) is transient, however [2]. Ingestion of a mixed-meal, and the ensuing rise in plasma AA and insulin, stimulates MPS and suppresses MPB leading to net accretion of protein, and a positive muscle NPBAL. In healthy, active adults, assuming adequate intakes of protein, periods of postabsorptive catabolism remain in dynamic equilibrium with periods of postprandial anabolism over a 24hr period, and muscle mass is maintained. This is likely true in fully grown adults in their third decade of life and onward into their fourth and possibly the fifth decade; however, at a certain point, NPBAL begins to shift toward a net negative state, and muscle is slowly lost. This slow loss of muscle with aging is termed sarcopenia [3].

Exercise increases muscle protein turnover. Specifically, exercise, independent of nutrition, results in an increase in both MPS and MPB, but the increase in MPB outweighs that of MPS and thus resulting in a negative NPBAL. However, the consumption of protein is able to increase the MPS response and drive a positive NPBAL. Resistance exercise (RE) leads to the sensitization of the muscle protein translational machinery to the presence of AA for at least 24-48 h [4], resulting in an additive stimulation of MPS over that due to hyperaminoacidemia alone [5]. The increase in MPS following exercise is dependent on the type of exercise completed.
For example, RE is commonly associated with increases in muscle size, whereas endurance exercise (EE) is characterized by remodeling of the muscle towards a more oxidative phenotype. Initially, the stress of RE and EE in untrained adults upregulates myofibrillar and mitochondrial protein synthesis [6]; however, as training progresses the response is refined to be more specific to form, resistance or endurance, of exercise. An acute bout of RE after 10 weeks of resistance training (RT) increased myofibrillar but not mitochondrial protein synthesis [7]. In contrast, acute EE increased mitochondrial protein synthesis after 10 weeks of endurance training, with no detectable effect on the myofibrillar sub-fraction [7]. Post-exercise protein intake supports the synthesis of proteins in these exercise-responsive protein sub-fractions [7]. These data underscore the importance of measuring fraction-specific protein turnover to understand the specificity of skeletal muscle adaptation.

It is now possible to combine stable isotopes with liquid chromatography and mass spectrometry to investigate the fractional synthesis rate and abundance of hundreds of individual proteins within a given muscle sub-fraction [8,9]. Determining the abundance and synthesis rate of individual proteins also permits the calculation of protein breakdown rates. Once changes in individual protein abundance and FSR are obtained by D2O ingestion and alanine labeling, the absolute rate of individual protein breakdown can be calculated by difference. This allows researchers to circumvent issues associated with bulk MPB measurements using the tracer dilution technique (i.e. the need for a physiological steady-state) and multiple biopsies during the dilution of the tracer [10,11]

In this review, we focus on the application of stable isotope tracers to elucidate the impact of protein ingestion and exercise on skeletal muscle protein turnover in humans (Fig. 1). Specifically, we consider the influence of total protein intake, protein source, and daily protein distribution on muscle protein synthesis and, where data are available, muscle protein breakdown. Given the breadth of information on this topic and the consideration of distinct clinical populations in accompanying reviews in this special issue, we limit our discussion primarily to healthy young and older adults without existing clinical comorbidities.

2. Protein dose
2.1. Protein distribution
2.2. Individual/per-feed protein dose
2.3. Total protein dose
2.4. Protein timing surrounding resistance exercise

3. Protein quality
3.1. Leucine: the trigger amino acid
3.2. Plant-derived sources

4. Muscle protein breakdown
4.1. Insulin
4.2. ‘Excess’ protein consumption

5. The role of adjunctive nutritional compounds to stimulate MPS
5.1. Omega-3 polyunsaturated fatty acids (n3-PUFA)
5.2. Collagen
5.3. Creatine

6. Conclusion

Skeletal muscle protein turnover has been, and remains, an important field of study. Muscle mass is determined by the difference between MPS and MPB, creating either a positive (anabolic state) or negative (catabolic state) NPBAL (summarised in Fig. 4). Through the use of labeled stable isotopes researchers have been able to determine the optimal dose, timing, distribution, and composition of a protein source to maximally stimulate MPS, inhibit MPB and thus create a positive NPBAL, as summarised in Table 3. An exciting avenue of future research exists in exploring the ability of nutritional supplements, other than protein/AA ingestion, to stimulate MPS, such as the use of omega 3 fatty acids. Furthermore, it is now possible to combine stable isotopes (D2O) with proteomic mass spectrometry to investigate the protein fractional synthesis rates and abundance of hundreds of individual proteins within a given muscle sub-fraction. This can also allow the calculation of the breakdown rate of these individual proteins, which would be extremely valuable information. The integration of stable isotopes and the emerging omics field will enable researchers to further elucidate the ability of nutritional interventions to influence biological networks that regulate muscle protein metabolism.


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Fig. 1. Schematic representation of the use of AA stable isotope tracers and D2O for the measurement of muscle protein turnover. (A) To measure acute (typically 0e6 h post-exercise and/or feeding) MPS, stable AA isotope tracers are infused intravenously which results in an increased plasma enrichment of the isotope. The AA isotope is taken up by the muscle (rate of disappearance) into the intracellular AA pool. The labeled AA is incorporated into new proteins (MPS). As infusion time progresses the change in incorporated AA stable isotope is proportionate to the rate of total MPS. Alternatively, MPB can be measured through the release of labeled AA stable isotope into the intracellular AA pool or inferred from the rate of appearance of the labeled AA into the venous blood samples. (B) To measure integrated (free-living) MPS D2O is ingested and results in an increase in the enrichment of the body water pool. Once entering the cell the deuterium becomes incorporated into alanine during the transamination process, these deuterium-labeled alanine AA are then incorporated into new muscle proteins and are indicative of MPS. (C) For both methods, muscle protein/plasma/saliva enrichment is determined using mass spectrometry following derivatization of AA. To calculate the rate of MPS, the enrichment of one muscle sample (T1) is subtracted from the enrichment of a later muscle sample (T2) and divided by the mean enrichment of the precursor (plasma enrichment when using stable AA isotope; body water enrichment when using D2O) multiplied by the time.
Screenshot (7386).png


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Fig. 2. Dose-response of muscle protein synthesis, to protein ingestion following exercise. Protein ingestion after (A) resistance exercise and (B) endurance exercise presented as a percent change from the ingestion of no protein (0 g) results in an increase in myofibrillar FSR. Following RE the consumption of 40 g versus 20 g of whey protein increased myofibrillar FSR only slightly and the increase was statistically significant indicating that 20 g of protein maximally stimulated MPS following RE (A). Following endurance exercise, 45 g of carbohydrates were consumed with 0 g, 15 g, 30 g, and 45 g of intrinsically labeled milk protein. Myofibrillar FSR was maximally stimulated with the ingestion of 45 g of carbohydrates and 30 g of protein, the consumption of 15 g of protein did not significantly increase MPS rates above that of the consumption of 0 g of protein. The figure was altered from Stokes and colleagues 2018 [37], data re-drawn from Witard and colleagues 2014 [34] and Churchward-Venne and colleagues 2020 [36].
Screenshot (7387).png

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Fig. 3. Muscle protein synthesis is increased following a bout of resistance exercise. The skeletal muscle becomes more sensitized to the ingestion of protein for at least 24 h following resistance exercise. Thus, total protein intake rather than the exact time at which protein is consumed surrounding resistance exercise has the greatest impact on muscle protein synthesis. Figure originally from and has been re-drawn from Churchward-Venne and colleagues [57].
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Fig. 4. Chronic (free-living) MPS and acute MPS/MPB can be quantified by the infusion of isotope tracers such as D2O and labeled AA, respectively. In a fasted state MPB is greater than MPS and thus the muscle is in a catabolic state of negative NPBAL. However, following exercise and an increase in dietary intake, specifically protein, MPS increases, MPB is inhibited and the muscle is in an anabolic state of positive NPBAL. Specifically manipulating dose, timing, distribution, and composition of protein intake can maximize the muscle's anabolic response.
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