Muscle Protein Synthesis Increases Muscle Growth and Muscle Mass

What is Muscle Protein Synthesis?

Muscle protein synthesis refers to the biochemical pathways your muscles use to rebuild and recover from exercise (as well as regular everyday physical activity).⁽¹⁾ Muscles are actually organized collections of cells made up of specialized proteins:

• myofibrillar – contractile proteins
• sarcoplasmic – the gel within the cell
• mitochondrial – muscle cell energy factory

As a result of various environmental factors, your muscle proteins are going through a constant cycle between muscle protein breakdown (MPB) and muscle protein synthesis (MPS).⁽²⁾

The goal of exercising our muscles is to be as strong, powerful, and as healthy as possible -- we want to be able to maintain or even build our strength for optimum health.

As we age, however, these goals may still be on the list, but muscle loss becomes accelerated, increasing the risk of health decline on top of impinging on the muscle-building process.⁽³⁾ To prevent many of the problems that often accompany the aging process, we ultimately need to minimize muscle loss.

Our muscles are usually going through some level of muscle protein breakdown at all times. Sometimes MPB is increased, sometimes it is decreased; it ultimately depends on the environmental factors at play.

Have you ever noticed the size of someone’s arm after it comes out of a cast?

That's the muscle breakdown effect at work and it literally happens within a week of limited muscle use. Your muscles are in a constant state of flux where about 1% of muscle protein is turned over daily -- ultimately, your body uses the amino acids generated from broken down muscle protein for other purposes.⁽⁴⁾

This creates a general cycle where muscle proteins are broken down and used by the body during fasting. Then when protein feeding occurs, these proteins are replaced by turning on muscle protein synthesis.

Usually, there is a steady-state where net amounts of muscle are neither gained nor lost. These dynamics and responses are different in different age groups, health, activity level, foods that are eaten, and genetics.

The muscle growth algorithm:

• If MPS is greater than MPB you gain muscle.
• If MPS is equal to MPB then your lean muscle mass remains the same.
• If MPB is greater than MPS you are losing muscle.

So, how do we know that any of this happens in the first place? The science behind untangling the riddles of muscle protein synthesis and muscle growth is quite interesting.

Beyond dissecting the muscle and looking at it under more and more powerful microscopes, scientists can now measure the dynamics of muscle protein synthesis by labeling amino acids with isotopes.⁽⁵⁾

Trained and untrained individuals, young and old, are put through a variety of exercise regimes and scientists take biopsies of their muscles several times throughout the sessions. From this, they then measure and determine the responses to exercise, nutrition, fasting, and a combination of these factors.

How Does Exercise Affect MPS?

“Adaption” is a muscle’s response to exercise. Muscle adaptation depends on several factors, including force, intensity, duration, and exercise type, however, genetics also plays a role.⁽⁶⁾

We have all heard of athletes that are genetically gifted -- this means that some respond more, and others less, to the same exercise. Though it's an unfortunate truth, some individuals are just better suited than other when it comes to how their body responds to exercise.

One reason you need variance in your exercise routine is to enable muscles to achieve an “all-around” adaptation -- Timmons demonstrated this scientifically by examining how muscles adapt in different individuals.⁽⁷⁾

Different types of exercise stimulate the various types of muscle proteins that we spoke about earlier (myofibrillar, sarcoplasmic, mitochondrial) in different ways.

With exercise, both MPS and MPB increase. The extent to which each increases, however, ultimately depends on the type of exercise, the intensity, and the duration.

After resistance training, myofibrillar protein synthesis is specifically increased -- myofibrillar proteins are the ones that produce muscle contractions.⁽⁸⁾

Conversely, after endurance training, mitochondrial protein synthesis in the muscle is increased whereas myofibrillar protein synthesis is not -- mitochondrial proteins are responsible for energy production.

Increases in myofibrillar MPS are specific to resistance exercise (weightlifting) and results in the net positive growth of the muscle -- something we call muscle hypertrophy.

The magnitude of muscle protein synthesis that results from resistance exercise is dependent upon both workload and the intensity. For example, at intensities ≤40% of one-repetition maximum (1-RM), there is no detectable increase in MPS.

It's when you begin to lift at intensities and loads greater than 60% 1-RM that resistance exercise can increase MPS 2- to 3-fold.⁽⁹⁾ Scientists think the ideal workload zone is in the range of 70-90%.

This does not mean that lifting lighter loads is worthless; however, it must be done in a very particular way in order to produce anabolic effects.

Failure is key!

Indeed, increases in MPS at 30% 1-RM can have comparable results to 90% 1-RM BUT only when exercise is performed to failure.⁽¹⁰⁾ This has to be stressed, if the workload is the same but you don't go to failure at 30% 1-RM, you do not get the same effects.

In essence, this means that increasing the volume of work at a lower intensity can overcome and even surpass the blunted MPS response of low-intensity exercise, but only if failure is attained.

Eccentric vs Concentric Contractions and MPS

Muscles go through 2 types of contractions. Eccentric contractions are when the muscles lengthen and resist force. Concentric contractions, on the other hand, are when the muscle contracts and shortens.

In a bicep curl, bringing the weight up to you is the concentric contraction and lowering it back down is eccentric.

An eccentric contraction is not necessarily a “negative” contraction. It is simply the muscle resisting a force as it is stretched. Eccentric-type exercise training has been shown to result in greater muscle hypertrophy than concentric type training.⁽¹¹⁾

But don’t jump to conclusions… there's more.

Measurement of muscle protein synthesis after both concentric and eccentric contractions has demonstrated only minimal differences.⁽¹²⁾ Moreover, when the total amount of work is matched between eccentric and concentric contractions there is no difference in training-induced muscle hypertrophy.⁽¹³⁾

It appears that the increased work caused by slowed eccentric contractions (negatives) may explain the greater efficacy of eccentric training, rather than contraction mode per se.

Summary – it is not the type of contraction that makes one type of contraction better than another in producing increased muscle growth. Rather, it is the increased amount of workload created by the increased time of contraction of a slow negative that is responsible for it.

Latency Period and Exercise

MPS is stimulated after exercise. The time between the end of the exercising and the start of muscle protein synthesis is called the latency period. The degree of intensity and the amount of time involved in the exercise will affect when MPS kicks in.

When you work out very hard and intensely, it may take several hours before muscle protein synthesis starts -- Cuthbertson showed that MPS remained stagnant for up to 3 hours after extremely fatiguing and damaging eccentric contractions.⁽¹⁴⁾

The latency period for lower intensity exercise is much shorter (6 × 8 repetitions at 75% 1-RM) is <1 h. After this latent period, MPS rises sharply for between 45 and 150 min and may be sustained for up to 4 h if the athlete has not eaten a protein-containing meal.⁽¹⁵⁾

However, In the presence of increased amino acid availability -- this is a scientist's way of saying the athlete consumes protein -- muscle protein synthesis can remain active for up to and beyond 24 h. This leads us to the effect of nutrition, and specifically protein, and its effect on muscle growth.

Nutrition and Muscle Protein Synthesis

Anabolism is the building of larger biologic molecules from smaller ones. It is the basis of building muscle.

The anabolic effects of nutrition are principally driven by the transfer and incorporation of amino acids acquired by consuming dietary protein, into skeletal muscle proteins.

In the early ’90s, researchers found that the key nutritional component for stimulating muscle protein synthesis from any meal was the amino acids contained in the meal.⁽¹⁶⁾

Since that time, other researchers have discovered that the effect of consuming protein on muscle protein synthesis is dose-dependent, meaning that both the amount and type of protein you eat affect how much MPS results.^(17)(18)

The Type of Protein is Critical

Different proteins have different amino acid quantities and these directly impact the level of muscle protein synthesis. To date, most research suggests that whey is the best type of protein when it comes to maximally stimulating muscle protein synthesis.

Studies over the last 10 to 15 years seem to have put a limit on how much protein can be used to stimulate MPS -- 20-25 grams is the number that's been most frequently cited.

Newer research, however, contradicts this paradigm and when exercise is combined with protein supplementation, it appears that the dosing limits may have been underestimated.⁽¹⁹⁾ So in short, 40 grams of protein is superior to 20 grams -- the higher the quality, the better the results.

When you consume a protein meal high in essential amino acids, and especially high in branched-chain amino acids, the anabolic MPS response is strong, yet occurs for a set period of time.

This makes sense, as you cannot simply grow your muscles by overeating quantities of chicken and steak, though it would be nice.

Thirty minutes after you eat a protein meal, there is a large increase (∼3-fold) in muscle protein synthesis. MPS will then peak at around 90 minutes before returning to its normal state in 2 hours.⁽²⁰⁾

Though the level of circulating amino acids and sustained ‘anabolic signaling’ may remain high, MPS returns to normal. At this point after eating, the muscle becomes full and no additional effect occurs in spite of sustained elevated amino acid levels.

Carbohydrates and MPS

How do carbohydrates factor into MPS?

The short answer – they don’t.

The intake of carbohydrate with protein affords no greater anabolic effects on muscle gains -- it doesn't help to further increase MPS nor does it aid in decreasing MPB after exercise.

This emphasizes the central role of amino acids as the principal (and perhaps only) macronutrients required to optimize the body's anabolic responses to weight lifting.⁽²¹⁾

Yes, carbs have other effects that are beneficial for sports performance and sports nutrition, however, in the context of this particular topic, they do not induce or play a significant role in MPS.

Insulin Decreases Muscle Protein Breakdown

While it is noteworthy that the provision of protein alone (i.e. without carbohydrate) causes a rise in insulin similar to that seen following a meal of carbohydrate, protein and fat, insulin apparently does not contribute to the anabolic effects that essential amino acids have on muscle protein synthesis.⁽²²⁾

It is commonly thought that the effect of insulin is to increase the uptake of amino acids in the muscle and stimulate MPS. This is actually not true and studies show that if insulin is blocked, the amino acids are still absorbed by the muscle and MPS continues.⁽²³⁾

However, insulin does have a very significant effect on muscle protein turnover in that it blocks muscle protein breakdown by 40-50%!

Thus insulin is not anabolic but rather it is anti-catabolic.

Thus, to summarize, essential amino acids regulate anabolic muscle growth via large increases in muscle protein synthesis. Insulin, on the other hand, regulates anti-catabolic (depressions in MPB) responses. Therefore, protein nutrition is the major driving force stimulating MPS while simultaneously decreasing MPB. The result is a significant net increase in muscle growth.

Protein and Exercise Magnify MPS

Combining optimum nutrition with exercise has a much greater effect on muscle protein synthesis than either protein consumption or exercise has on MPS alone.

If you are reading this blog, this is probably something that you have already figured out on your own.

This is exemplified by the fact that acute increases in muscle protein synthesis after exercise in the absence of adequate intake of protein will be overshadowed by a prolonged rise in muscle protein breakdown.⁽²⁴⁾

Remember, the battle is always between muscle breakdown and synthesis and without adequate protein intake, the muscle breakdown forces will outweigh the muscle gain forces. This results in a net muscle loss also called negative nitrogen balance.

You can't build or remodel muscle without amino acids!

When you increase the dietary essential amino acid availability after exercise, the magnitude and duration of MPS is significantly increased. Therefore, in essence, exercise is able to pre-condition muscle to delay the muscle full ‘set point’.⁽²⁵⁾

This is a key factor and why we always recommend to athletes that they take high-quality whey protein following training or competition

Dioxyme Ultra Whey

Grass-fed whey isolate + concentrate for maximal MPS with digestive enzymes for improved digestion and absorption

Learn More

mTOR and Muscle Protein Synthesis

mTOR is one of the keys that unlocks the MPS gate.

The science is fascinating and intuitively supports everything you see in athletics: power athletes are more muscular with less endurance, and endurance athletes are less muscular with greater endurance.

mTOR is an acronym for the mammalian target of rapamycin pathway and is a key signaling mechanism affecting exercise/nutrient-induced changes in muscle protein synthesis.⁽²⁶⁾

Activation of mTOR stimulates other factors such as 4E-binding protein (4EBP1), ribosomal protein S6 kinase (p70S6K1), 4 G/A/B (eIF4G/A/B) that are involved in the biochemical pathways of muscle protein synthesis.⁽²⁷⁾

In a parallel pathway, activation of eukaryotic initiation factor 2B (eIF2B) helps carry a transfer-RNA molecule to RNA and helps further stimulate protein synthesis.⁽²⁸⁾

We have all heard of IGF-1 (insulin growth factor) and its effects on muscle growth. Studies have demonstrated that this happens as a result of IGF-1 stimulating mTOR via the IGFr-AKT-mTOR pathway.

However recent studies seem to indicate that systemic IGF-1 levels may not have as much effect as thought.⁽²⁹⁾ These data suggest that the systemic induction of IGF-1 is not a pivotal part of the adaptive process. Nonetheless, it could be argued that IGF-1 regulates AKT–mTOR signaling via localized cell-to-cell signaling mechanisms.

New research has shown that phospholipase D (PLD) and phosphatidic acid (PA) play a biochemical role as well in muscle protein synthesis. These reactions may happen prior to the mTOR stimulation that results from muscle contractions.

This is why phosphatidic acid is a key ingredient in MPO -- it's another stimulus to muscle protein synthesis.

During endurance exercise, mitochondrial protein synthesis is stimulated via 5′-AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor γ coactivator (PGC-1) pathway.

In the muscle, the energy molecule ATP (adenosine triphosphate) donates phosphate molecules for cellular energy and the result is a build-up of AMP (adenosine monophosphate) which stimulates the production of AMPK resulting in mitochondrial protein synthesis, not muscle protein synthesis.

Increases in PGC-1 also leads to mitochondrial protein synthesis.⁽³⁰⁾

Further, the activation of both AMPK and PGC-1 together inhibits MPS and stimulates MPB.

A mouthful yes, but endurance exercise puts different demands and creates different effects on the muscle.

The takeaway: Resistance exercise biochemically increases muscle protein synthesis. Endurance exercise decreases MPS and stimulates MPB.

The Role of Leucine in MPS

Amino acid metabolism in skeletal muscle is limited to six amino acids (glutamate, aspartate, asparagine, and the three BCAAs). Among these amino acids, the most noteworthy effects have been observed with the branched-chain amino acid leucine.

Increased levels of leucine within the muscle cell stimulate protein synthesis via mTOR-dependent and mTOR independent pathways.

Leucine stimulates muscle protein synthesis by mTOR activating initiation factors eIF4E and rpS6. Interestingly, plasma levels of leucine do not decrease after resistance exercise. Net protein balance remains negative after resistance exercise, as protein breakdown is greater than protein synthesis, and remains negative until dietary protein or leucine is ingested.⁽³¹⁾

Dietary branched-chain amino acids reach the bloodstream virtually unaltered from their levels in the diet; thus, leucine reaches peripheral tissues in direct proportion to its dietary intake.

During exercise, there is also an increased release of leucine from the liver and gut and movement into skeletal muscle. This pattern of inter-organ movement of amino acids provides for a continuous supply of leucine to skeletal muscle necessary to maintain some MPS.

Different proteins and different quality whey proteins vary in how much leucine they provide. Grass-Fed Ultra Whey contains 6.4 grams of natural BCAA per serving.

Testosterone and Muscle Protein Synthesis

Testosterone can play a very significant role in MPS. Various studies show that testosterone greatly increases muscle hypertrophy and muscle protein synthesis by as much as 27%.⁽³²⁾

It seems that testosterone positively affects mTOR in how it regulates protein synthesis. Low testosterone signals a decrease in muscle protein synthesis. This does make logical sense.

One thing that can especially plague men as they get older is a lower T-count which correlates with their difficulty of increasing or even maintaining muscle mass and strength. When testosterone is given to men and women, muscle protein synthesis and muscle mass increases

Wrap Up

Muscle protein synthesis is the key to increased muscle growth and strength. It is the critical element behind gaining lean mass. If you want to maximize your muscular growth, strength and athletic performance, you need to eat like a power athlete and train like a power athlete.

• References
  1. “Muscle protein synthesis in response to nutrition and exercise” Atherton, P.J., Smith, K. The Journal of Physiology. Jan. 2012.
  2. “Role of insulin in the regulation of human skeletal muscle protein synthesis and breakdown: a systematic review and meta-analysis”Abdulla, H., Smith, K., Atherton, P.J., Idris, I. Diabetologia. Sep. 2015.
  3. “Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis”Fry, C.S. et al. Skeletal Muscle. Mar. 2011.
  4. “Human muscle protein synthesis and breakdown during and after exercise”Kumar, V., Atherton, P., Smith, K., Rennie, M.J. Journal of Applied Physiology. Jun. 2009.
  5. “A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly”Katsanos, C.S., Kobayashi, H., Sheffield-Moore, M., Aarsland, A., Wolfe, R.R. American Journal of Physiology, Endocrinology, and Metabolism. Feb. 2006.
  6. “Exercise Metabolism and the Molecular Regulation of Skeletal Muscle Adaptation”Egan, B., Zierath, J.R. Cell Metabolism. Feb. 2013.
  7. “Variability in training-induced skeletal muscle adaptation”Timmons, J.A. Journal of Applied Physiology. Mar. 2011.
  8. “Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle”Wilkinson, S.B., et al. The Journal of Physiology. Jul. 2008.
  9. “Human muscle protein synthesis and breakdown during and after exercise”Kumar, V., Atherton, P., Smith, K., Rennie, M.J. Journal of Applied Physiology. Jun. 2009.
  10. “Low-Load High Volume Resistance Exercise Stimulates Muscle Protein Synthesis More Than High-Load Low Volume Resistance Exercise in Young Men”Burd, N.A., et al. PLOS One. Aug. 2010.
  11. “The effects of eccentric versus concentric resistance training on muscle strength and mass in healthy adults: a systematic review with meta-analysis”Roig, M., O’Brien, K., Murray, R., McKinnon, P., Shadgan, B., Reid, W.D. British Journal of Sports Medicine. Aug. 2009.
  12. “Eccentric resistance training increases and retains maximal strength, muscle endurance and hypertrophy in trained men”Coratella, G., Schema, F. Applied Physiology, Nutrition, and Metabolism. Aug. 2016.
  13. “Similar increases in muscle size and strength in young men after training with maximal shortening or lengthening contractions when matched for total work”Moore, D.R., Young, M., Phillips, S.M. European Journal of Applied Physiology. Apr. 2012.
  14. “Muscle protein synthesis in response to nutrition and exercise”Atherton, P.J., Smith, K. The Journal of Physiology. Jan. 2012.
  15. “Muscle protein synthesis in response to nutrition and exercise”Atherton, P.J., Smith, K. The Journal of Physiology. Jan. 2012.
  16. “Flooding with L-[1-13C]leucine stimulates human muscle protein incorporation of continuously infused L-[1-13C]valine”Smith, K., Barua, J.M., Watt, P.W., Scrimgeour, C.M., Rennie, M.J. American Journal of Physiology. Mar. 1992.
  17. “Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle”Cuthbertson, D., et al. FASEB. Mar. 2005.
  18. “Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in young men”Moore, D.R. American Journal of Clinical Nutrition. Dec. 2008.
  19. “The response of muscle protein synthesis following whole‐body resistance exercise is greater following 40 g than 20 g of ingested whey protein”Macnaughton, L.S., et al. Physiology Reports. Aug. 2016.
  20. “Muscle protein synthesis in response to nutrition and exercise”Atherton, P.J., Smith, K. The Journals of Physiology. Jan. 2012.
  21. “Co-ingestion of carbohydrate with leucine-enriched essential amino acids does not augment acute postexercise muscle protein synthesis in a strenuous exercise-induced hypoinsulinemic state”Kato, H., et al. BMC. Aug. 2016.
  22. “Muscle protein synthesis in response to nutrition and exercise”Atherton, P.J., Smith, K. The Journal of Physiology. Jan. 2012.
  23. “Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle”Greenhaff, P.L., Karagounis, L.G., Peirce, N., Simpson, E.J. Endocrinology and Metabolism. Jun. 2008.
  24. “Increased rates of muscle protein turnover and amino acid transport after resistance exercise in human”Biolo, G., Maggi, S.P., Williams, B.D., Tipton, K.D. The American Journal of Physiology. Mar. 1995.
  25. “Muscle protein synthesis in response to nutrition and exercise”Atherton, P.J., Smith, K. The Journal of Physiology. Jan. 2012.
  26. “Leucine-Enriched Nutrients and the Regulation of mTOR Signalling and Human Skeletal Muscle Protein Synthesis”Drummond, M.J., Rasmussen, B.B. Current Opinion in Clinical Nutrition and Metabolic Care. May. 2008.
  27. “Mammalian Target of Rapamycin Complex 1 Activation Is Required for the Stimulation of Human Skeletal Muscle Protein Synthesis by Essential Amino Acids”Dickinson, J.M., et al. The Journal of Nutrition. Mar. 2011.
  28. “Recent progress toward understanding the molecular mechanisms that regulate skeletal muscle mass”Goodman, C.A., Mayhew, D.L., Hornberger, T.A. Cellular Signalling. Dec. 2011.
  29. “Growing collagen, not muscle, with weightlifting and ‘growth’ hormone”Burd, N.A., West, D.W.D., Churchward-Venne, T.A., Mitchell, C.J. The Journal of Physiology. Jan. 2010.
  30. “The role of PGC‐1 coactivators in aging skeletal muscle and heart”Dillon, L.M., Rebelo, A.P., Moraes, C.T. International Union of Biochemistry and Molecular Biology. Jan. 2012.
  31. “Leucine Regulates Translation Initiation of Protein Synthesis in Skeletal Muscle after Exercise”Norton, L.E., Layman, D.K. The Journal of Nutrition. Feb. 2006.
  32. “Effect of testosterone on muscle mass and muscle protein synthesis”Griggs, R.C., Kingston, W., Jozefowicz, R.F., Herr, B.E., Forbes, G., Halliday, D. Journal of Applied Physiology. Jan. 1989.