# The Science Behind: SynthePURE - Whey Protein Isolate



## Big A (Aug 7, 2011)

The Science Behind: ‘SynthePURE – Whey Protein Isolate’ | Synthetek


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## PRIDE (Feb 17, 2012)

SynthePURE™ is a Whey Protein Isolate fashioned through a process performed at a much lower temperature than is typical for whey protein manufacture. During this process the protein powder is thoroughly filtered resulting in a high purity end product. The lower temperature has the effect of preserving the fragile biologically active peptides, lactoferrin, and immunoglobulins found in whey. The result is a whey protein powder devoid of denaturation with no loss of biological activity.

Protein is the essential centerpiece around which all other factors connect to promote anabolism. This article will focus on protein metabolism and the role the various hormones play in complementing each other in inducing anabolism. SynthePURE™ is the substrate upon which all of the factors work in effecting net muscle protein synthesis. We will examine in a highly readable (non-technical) manner the significance of:

    Insulin
    Growth Hormone
    Amino Acid Pool
    Exercise
    Blood Flow
    IGF-1
    IGF-1 bound to IGFBP-3
    Androgens
    Thyroid Hormones

None of these factors are capable of bringing about muscle tissue accrual by themselves. Instead these factors complement each other and do so by facilitating the reduction of the breakdown or promotion of the synthesis of muscle protein. Some factors are only capable of positively effecting retainment or uptake of a single crucial amino acid while others have multifaceted roles to play. Most of these factors are not anabolic by themselves. Rather they contribute specific necessities to a central pool that together maximize anabolism. All of these factors modulate amino acids which come from protein.

*The Centerpiece – Protein*

Quality

Infant formulas rely on bovine whey protein to mimic the nutritional content of human milk. Of critical importance in substituting for human milk is the inclusion of the highly nutritious alpha-Lactalbumin protein found in whey. Both bovine and human alpha-Lactalbumin contain very high amounts of the essential amino acids (tryptophan, phenylalanine + tyrosine, leucine, isoleucine, threonine, methionine + cysteine, lysine and valine). Of primary importance are the significant quantities of lysine, cysteine and tryptophan contained in alpha-Lactalbumin1. Unfortunately the processing through which protein undergoes in creating a humanly consumable product harms some of these amino acids. Tryptophan is a particularly unstable amino acid, and the heating of proteins at excessive temperatures will cause major reductions in tryptophan bioavailability 2. In addition the reaction between nitrogenous side chains of the amino acids and reducing sugars usually brings about a deterioration of the nutritional quality of the protein and lysine in particular is often lost. Lysine, tryptophan and methionine residues also react with oxidizing lipids and cause losses in the availability of lysine, tryptophan and sulfur-containing amino acids 3.

The important point is simply if loss of protein bioavailability is unacceptable for infant nutrition it should also be unacceptable to those seeking body transformation.

In the literature there has been considerable interest in the proposition that proteins of different biological quality and digestibility might be more or less efficient at supplying amino acids to muscle after exercise. Recent studies 4,5 seem to demonstrate that whey proteins are superior to casein and soy in supplying amino acids for net muscle protein accretion.

Quality protein is the centerpiece around which tissue accrual evolves.

Why is protein the centerpiece?


“The metabolic basis for skeletal muscle growth lies in the relationship of muscle protein synthesis to muscle protein breakdown. Muscle hypertrophy occurs only from net protein synthesis; that is, when muscle protein synthesis exceeds breakdown….resistance exercise, has a profound effect on muscle protein metabolism, often resulting in muscle growth. Acutely, resistance exercise may result in improved muscle protein balance, but, in the absence of food intake, the balance remains negative (i.e., catabolic). …Amino acid availability is critical to the control of muscle protein metabolism. Thus, a meal or a supplement containing protein or amino acids will influence muscle protein. …[and if] ingested after exercise should result in muscle anabolism.” – Kevin Tipton 6


Normally meals induce a transient increase in muscle protein synthesis (MPS) followed by muscle protein breakdown (MPB). In this manner tissue is maintained but there is no net protein synthesis thus no anabolism.







The authors of the Tipton study from which the above quote derives established therein that ingestion of either whey protein or casein protein after exercise led to “increases in muscle protein net balance, resulting in net muscle protein synthesis despite different patterns of blood amino acid responses” 6.

The general consensus from research in this area is that exercise induces protein degradation as well as protein synthesis. Ingestion of protein during this time period strongly tips the balance of degradation versus synthesis to that of overall protein synthesis.






There really is very little to be gained by spending a lot of time discussing the details of numerous studies which examine such things as:

    Digestion Rate: Whey versus Casein and EAA (essential amino acids); and
    Timing: pre-workout versus during and post-workout

Making Whey digest slowly

Most of the variability between the various protein sources lies in the digestion rate. Whey is a fast digesting protein and can be made to behave like the even speedier essential amino acids (EAA) by simply ingesting whey a little earlier. This is an effective pre-workout approach. Like-wise if a slower digestion rate is desired co-ingestion of viscous gels and soluble dietary fibers such as psyllium, pectin, guar gum and ispaghula will slow amino acid release either by increasing the time needed for intestinal absorption or slowing the rate of gastric emptying 7-11. In this manner whey can be made to behave as the slower releasing soy and casein proteins.

So while whey protein can be made to behave more like casein, casein can not be made to behave like whey.

Just ingest it

Exercise and whey protein are anabolic no matter when ingested. The effect whey protein has on anabolism can be explained through the microscope. A more comfortable approach though is to simply back away from all of the details many of which have yet to be elucidated and focus on a natural discussion of those familiar factors that ultimately influence protein metabolism at the microscopic level. That is the approach we will follow. But since we have the microscope in front of us lets take a quick look.

The regulation of skeletal muscle protein turnover is complex. It involves the interactions of gene transcription (i.e. obtaining the assembly instructions) and the subsequent translational control of protein synthesis (i.e. the assembly of the protein from its constituent parts, amino acids). The primary translation pathway leading to protein synthesis is mTOR (mammalian target of rapamycin). In order to build proteins, translation needs to occur and this is initiated by many factors and signaling molecules which feed into this complex regulator called mTOR.

mTOR is a key regulator of translational control. Nutrient, hormonal, and contractile stimuli primarily converge at this protein making mTOR an important modulator of protein synthesis. So when we back away from the microscope and discuss hormones such as insulin, IGF-1 and growth hormone and factors such as exercise, blood flow and protein ingestion what we should be vaguely aware of is that these hormones and factors are in part converging on mTOR to activate those positive regulators of mTOR and protein synthesis or deactivate those negative regulators (or inhibitors) of mTOR and subsequent protein synthesis.

There is no need to examine the specifics and so the following image is meant to convey a very general understanding of the complexity inside the cell.






A recent study in humans using muscle biopsies, tissue processing, western immunoblot analysis and maybe a microscope as well concluded that resistance exercise rapidly increases mTOR signaling, and whey protein increases and prolongs the mTOR signaling response to exercise and training 12.

Simply stated whey protein following exercise increases net protein synthesis which leads to anabolism. If you have a microscope you can add “through mTOR”.
References:

1 – Heine, Willi E., The Importance of alpha-Lactalbumin in Infant Nutrition, J. Nutr. 121: 277-283, 1991
2 – Cug, J. L. & Friedman, M. (1989), Effect of heat on tryptophan in food: chemistry, toxicology, and nutritional consequences Absorption and Utilization of Amino Acids, (Friedman, M., ed.), vol. 3, pp. 103-115, CRC Press, Boca Raton, FL
3 – Nielsen, H. K., Finot, P. A & Hurrell, R. F. (1985), Reactions of proteins with oxidizing lipids: 2. Influence on protein quality and on the bioavailability of lysine, methionine, cyst(e)ine and tryptophan as measured in rat assays, Br. J. Nutr. 53: 75-86
4 – Hartman JW, Tang JE, Wilkinson SB, Tarnopolsky MA, Lawrence RL, Fullerton AV, Phillips SM, Consumption of fat-free fluid milk after resistance exercise promotes greater lean mass accretion than does consumption of soy or carbohydrate in young, novice, male weightlifters, Am J Clin Nutr 86: 373–381, 2007
5 – Wilkinson SB, Tarnopolsky MA, Macdonald MJ, MacDonald JR, Armstrong D, Phillips SM, Consumption of fluid skim milk promotes greater muscle protein accretion after resistance exercise than does consumption of an isonitrogenous and isoenergetic soy-protein beverage, Am J Clin Nutr 85: 1031–1040, 2007
6 – Tipton, Kevin, et al., Ingestion of Casein and Whey Proteins Result in Muscle Anabolism after Resistance Exercise, Med Sci Sports Exerc. 2004 Dec;36(12):2073-81
7 – Rigaud, D., Effect of psyllium on gastric emptying, hunger feeling and food intake in normal volunteers: a double blind study, European Journal of Clinical Nutrition (1998) 52, 239-245
8 – Holt S, Heading RC, Cater DC, Prescott LF & Tothill P (1979): Effect of gel fibre on gastric emptying and absorption of glucose and paracetamol, Lancet 1, 636-639
9 – Blackburn NA, Redfern JS, Jarjis HA, Holgate AM, Hanning I & Scarpello JH (1984): The mechanism of action of guar gum in improving glucose tolerance in man, Clin. Sci. 66, 329-36
10 – Ralphs DNL & Lawaetz NJG (1978): Effect of a dietary fibre on gastric emptying in dumpers, Gut 19, A 986-987
11 – Schwartz SE, Levine RA, Singh A, Scheidecker JR & Track NS (1982): Sustained pectin ingestion delays gastric emptying, Gastroentero. 83, 812-817
12 – Hulmi, J. J., Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men, Appl Physiol 106: 1720–1729, 2009


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## PRIDE (Feb 17, 2012)

*Protein Metabolism – How various hormones create anabolism.*

A complete protein such as SynthePURE™ provides the raw materials (amino acids) for protein synthesis. We understand that anabolism only occurs when protein synthesis exceeds protein degradation/breakdown. Exercise creates an environment where anabolism is possible if protein is supplied. In that environment protein synthesis will exceed protein breakdown resulting in net tissue accrual.

However ultimate body transformation requires maximum anabolism. This is primarily achieved through the complementary interplay of those hormones that affect the components of protein metabolism. By understanding precisely how each hormone or factor affects the components responsible for the outcome of protein metabolism one can better achieve an anabolic response.

The primary components responsible for determining the outcome of protein metabolism are:

    Whole Body Protein Synthesis – synthesis throughout organs, non skeletal muscle & skeletal muscle
    Muscle Protein Synthesis – synthesis in skeletal muscle only
    Whole Body Protein Breakdown/Degradation – breakdown throughout organs, non skeletal muscle & skeletal muscle
    Muscle Protein Breakdown/Degradation – breakdown in skeletal muscle only
    Oxidation – amino acid breakdown & subsequent use for energy
    Amino Acid Transport into Cells – movement of amino acids into the cells for incorporation into protein chains

These components will be discussed in relation to the hormones and factors that manipulate them. We will examine the science behind these hormones so that by the end of this section we will understand for instance exactly how insulin and growth hormone relate to one another and how only as an ensemble are they truly anabolic.

The hormones and factors we will examine are:

    Insulin
    Growth Hormone
    Amino Acid Pool
    Exercise
    Blood Flow
    IGF-1
    IGF-1 bound to IGFBP-3
    Androgens
    Thyroid Hormones

For each paragraph the relevant science and studies will be briefly discussed and then summarized in bracketed bold. At the end of the section I will provide a handy table indicating in which direction each hormone affects each of the components of protein metabolism.

*Insulin*

There is indirect evidence that post-meal hyperinsulinemia [excess levels of circulating insulin] induces protein anabolism, other than through the suppression of whole-body proteolysis [i.e. protein breakdown/ catabolism], by facilitating the incorporation of dietary amino acids into new proteins. In fact, when post-meal hyperinsulinemia and hyperaminoacidemia [high insulin & high amino acids] are reproduced in normal subjects by a combined intravenous infusion of insulin and amino acids, the estimates of whole-body protein synthesis increase more than after amino acids alone 20.

[Insulin + Amino Acids = greater increase in entire body protein synthesis]

The stimulatory effect of hyperinsulinemia on whole-body protein synthesis cannot be demonstrated when insulin alone is infused 20-25. In this case, by reducing the rate of protein breakdown, hyperinsulinemia decreased the intracellular concentrations of most amino acids 26, limiting their utilization for protein synthesis 27.

[In other words the store of amino acids (often called the intracellular amino acid pool) is replenished in two ways: one by eating/ingestion of protein & the other by the breakdown of protein in muscle (i.e. protein degradation). This latter, protein degradation reduces protein to its constituent parts (amino acids) which will be transported outside the cell & either be further removed or remain in the amino acid pool (which resides between muscle cells) and is available for reuse in muscle for the next round of transport into muscle & new protein synthesis. Insulin reduces protein breakdown so the amino acid pools are not replenished.]

Branched-chain amino acids (Leucine, Isoleucine, Valine) are particularly sensitive to hyperinsulinemia 28 and it has been shown the insulin-induced suppression of plasma isoleucine concentration 29, i.e. of a single essential amino acid, is sufficient to decrease whole body protein synthesis.

[So in essence protein synthesis requires all the essential amino acids. If one is missing no protein synthesis will occur.]

The results of several studies demonstrate that the overall effect of insulin on the rate of change in whole-body proteins comes from the combined results of the differential effects of the hormone on the rates of protein breakdown and synthesis of individual proteins. For instance, despite the rate of whole-body proteolysis [breakdown] being decreased by insulin 20-25, the rate of muscle protein proteolysis is not affected by local hyperinsulinemia 30. Such a differential effect can be explained by the fact that insulin decreases the proteolytic activity of lysosomes [which are a degradation pathway acting throughout the body] but does not control the ubiquitin system [which is active in muscle breakdown] 31 that is responsible for the bulk of muscle proteolysis 31.

[So insulin decreases protein breakdown/degradation throughout the entire body but does not inhibit protein breakdown specifically in muscle.]

Insulin increases the amount of protein deposited in muscle by directly increasing the rate of protein synthesis (40-60% as measured by lysine & phenylalanine disappearance from intracellular pools). For the most part (two exceptions) Insulin does not increase (or regulate) transmember amino acid transport. Therefore transportation of amino acids is not a primary mediator of insulin anabolic actions in muscle 40.

[So Insulin's primary modes of action are reduction of whole-body protein breakdown as discussed already & in muscle an increase in the rate of protein synthesis. Insulin draws on the intracellular pool of amino acids to affect this increased synthesis. It is possible to run out of amino acids from that pool. Insulin can suck the reservoir dry so to speak. In addition insulin in general (there is an exception) does not increase the rate of transportation of amino acids across the cell membrane into the cell. That remains normal. But the benefit of insulin in muscle is that it increases protein synthesis. However other things are needed besides insulin to affect overall anabolism.]

Insulin draws on an existing intracellular pool of amino acids. When amino acid concentrations are maintained at levels higher than normal during systemic insulin administration insulin increased muscle protein synthesis 40.

[So anabolism occurs when both insulin increased protein synthesis occurs and amino acid levels are maintained higher then normal. The primary way to effect this is to increase amino acid/protein ingestion.]

Insulin does not significantly modify protein breakdown in muscle. It has been shown that, during adequate amino acid supply, the most important degradative system in muscle is an ATP-independent system that requires the presence of a specialized protein, termed ubiquitin. This system is not sensitive to insulin. Concerning protein breakdown insulin apparently plays a role only in the regulation of the lysosome activity. These intracellular organelles are not involved in the myofibrillar protein degradation in normal conditions, but only in the presence of low insulin levels or decreased amino acid availability) 31 .

[So again insulin will increase protein synthesis in muscle but will not inhibit protein breakdown. So in general anabolism will occur if more protein synthesis then protein breakdown occurs.]

Following protein degradation, the amino acids from the degradation event are either transported outward (or in the case of leucine oxidized) or are redirected back into protein synthesis. Phenylalanine & leucine have been shown to be redirected back into protein synthesis while lysine may not 30 .

Insulin induces hyperpolarization in the skeletal muscle cells by directly activating the sodium ion (Na+) and potassium ion (K+) -ATPase pump. Those amino acids which are strongly “attracted” to the electrochemical characteristics of the cell membrane are more readily taken up into muscle from the intracellular pool of amino acids. Alanine & lysine are two amino acids that have this attraction and are more readily drawn into muscle by insulin 30 .

[When protein in muscle is broken down and its constituents removed back to the amino acid pool, those amino acids may be removed from muscle pools entirely, may be reused for new synthesis or for some amino acids oxidized or used for energy. It would not benefit anabolism to lose the important amino acid leucine to oxidation. Insulin which in general doesn't increase transport of amino acids from the pool into cells, does so for a few amino acids which use NA+ & K+ channels, namely alanine & lysine.]

The branched-chain amino acids (leucine, valine, and isoleucine) and the aromatic (phenylalanine and tyrosine) are preferably transported through system L . This sodium-independent system is unable to generate high transmembrane gradients for its substrates. It has been shown that the kinetic characteristics of system L are not influenced by insulin 30.

[So insulin which has no effect on this mode of transport does not increase the uptake of some very important amino acids.]

Blood flow has been found to increase local amino acid delivery to muscle and secondarily increase amino acid transport. This effect may be responsible for increase in leucine uptake.

[This is an extremely important way in which amino acids are drawn to muscle and into cells. This important amino acid leucine has been shown to make its way into cells via increase in blood flow.]

Alanine synthesis (which is a function of pyruvate) also increases in the presence of insulin because insulin increases glucose uptake & intracellular pyruvate in muscle 30 .

[Certain amino acids can be synthesized from the breakdown of other amino acids. Alanine is one of them. Alanine is often used for energy and so protein synthesis rate or anabolism may depend on the availability of alanine not yet oxidized. The fact that insulin increases alanine synthesis is a desirable effect.]

The anabolic effect of insulin on muscle may have become self-limited because of an intracellular depletion of precursor amino acids for protein synthesis, unless amino acid transport is independently stimulated by other factors, i.e., amino acid administration 30 .

[Again an external source of amino acids is needed to make insulin anabolic in muscle.]
References:

20 – Castellino P, Luzi L, Simonson DC. Haymond M. DeFronzo RA. Effect of insulin and plasma amino acid concentrations of leucine metabolism in man: role of substrate availability on estimates of whole body protein synthesis. J Clin Invest 1987: 80:1784-9 3
21 – Fukagawa NK. Minaker KL. Rowe JW. Goodman MN. Matthews DE. Bier DM, et al. Insulin-mediated reduction of whole body protein breakdown: dose-response effects on leucine metabo¬ lism in postabsorptive men. J Clin Invest 1985:76:2306-11
22 – Tessari P, Trevisan R, Inchiostro S, Biolo G, Nosadini R, De Kreutzenberg SV, et al. Dose-response curves of effects of insulin on leucine kinetics in humans. Am J Physiol 1986;251:E334-42
23 – Tessari P. Nosadini R. Trevisan R. De Kreutzenberg SV. Inchiostro S. Duner E. et al. Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin dependent diabets mellitus: evidence for insulin resistance involving glucose amino acid metabolism. J Clin Invest 1986:77:1797-804
24 – Luzi L, Castellino P. Simonson DC, Petrides AS, DeFronzo RA. Leucine metabolism in IDDM: role of insulin and substrate availability. Diabetes 1990:39:38-48
25 – De Feo P. Volpi E, Lucidi P, Cruciani G. Reboldi G. Siepi D, et al. Physiological increments in plasma insulin concentrations have selective and different effects on synthesis of hepatic proteins in normal humans. Diabetes 1993:42:995-1002
26 – Alvestrand A, DeFronzo RA, Smith D, Wahren J. Influence of hyperinsulinaemia on intracellular amino acid levels and amino acid exchange across splanchnic and leg tissues in uraemia. Clin Sci 1988;74:155-63
27 – De Feo P. Haymond MW. Effect of insulin on protein metabolism in humans: methodological and interpretative questions. Diab Nutr Metab 1991:4:241-9
28 – Fukagawa NK. Minaker KL. Young VR. Rowe JW. Insulin dosedependent reductions in plasma amino acids in man. Am J Physiol 1986;250:E13-7
29 – Lecavalier L, De Feo P. Haymond MW. Isolated hypoisoleucinemia impairs whole body but not hepatic protein synthesis in humans. Am J Physiol 1991;261:E578-86
30 Biolo G, Declan Fleming RY. Wolfe RR. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest 1995:95:811-9
31 – Kettlehut IC. Wing SS. Goldberg AL. Endocrine regulation of protein breakdown in skeletal muscle. Diab Metab Rev 1988;4:751-72
40. – Bennett, W. M., A. A. Connacher, C. M. Scringeour, R. T. Jung, and M. J. Rennie 1990 Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia Am. J. PhysioL 259:E185-E194


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## PRIDE (Feb 17, 2012)

*Growth Hormone*

Growth hormone (GH) promotes protein anabolism with mechanisms different from insulin. It does not affect the rates of whole-body proteolysis [breakdown] but decreases those of amino acid oxidation 41,42 The sparing effect on amino acid oxidation results in a greater rate of their incorporation into proteins 41,42,47, with a net protein anabolic effect.

[So Growth Hormone decreases amino acid oxidation (or break down for energy). This should have the effect of preserving key amino acids in that very important amino acid pool. This means that muscle protein synthesis or even increased muscle protein synthesis induced by insulin will be prolonged because there will be a larger pool of raw material (aminos) to draw from.]

In the Copeland study 41 the specific effects of GH on protein metabolism were examined in isolation from insulin and IGF-1. Although in reality since GH leads to creation of IGF-1 six or so hours after release or administration it is not possible for a person to experience only those effects specific to GH.

From Copeland, “the most impressive finding of our study is that an acute infusion of growth hormone (GH) is associated with a prompt inhibition in leucine oxidation, a metabolic action independent of other hormonal changes. This observation, in the context of our study design, is of particular importance since previous studies examining the protein anabolic actions of GH may not have controlled for anabolic effects mediated by a secondary increase in insulin secretion. In our study, insulin levels were identical in control and GH treatment groups 41.

[Growth Hormone strongly inhibits the loss of leucine to oxidation leaving it available for protein synthesis.]

GH infusion was also associated with an increase in whole body protein synthesis 41. This observation of an acute increase in the rate of whole body protein synthesis supports the findings of Horber and Haymond 42, who also observed a stimulation of whole body protein synthesis in normal subjects and corticosteroid-treated subjects given GH chronically.

[Growth Hormone increases whole body protein synthesis.]

“Our data also suggest that the acute GH-induced increase in whole body protein synthesis occurs primarily in nonskeletal muscle tissues, as indicated by the directional changes in leucine and phenylalanine disappearance rates across the leg. GH treatment resulted in an hourly net accretion of 32 mg whole body protein but an hourly loss of 77 mg skeletal muscle protein (relative to baseline values). Assuming continued unperturbed biological action of GH (including confounding effects by IGF-I or insulin), this would translate to an average loss of 1.8 g skeletal muscle protein each day. It is well known, however, that GH treatment invariably is followed some 6-8 h later by a significant increase in blood IGF-I which may stimulate skeletal muscle protein anabolism.” 41

“By contrast Fryburg et al 43 demonstrated that GH infused directly into the brachial artery stimulates protein synthesis. This increase in muscle protein synthesis occurred only after a longer exposure to GH than the current study. In addition, in that study an increase in blood flow was observed, whereas in our study the systemic administration of GH was not associated with an increase in blood flow in the leg. Recently, these same investigators reported data on regional effects after a systemic infusion of GH, using a design similar to ours but without a concomitant infusion of somatostatin 44. They observed acute increases in forearm blood flow and amino acid uptake across the arm after GH, without evidence of increased protein synthesis in the whole body. However, increases in both insulin and IGFI concentrations were induced by the GH infusion, which may account for some of the differences observed between their studies and ours 44.”

The authors explained the likely reason for the discrepancy by noting that the period of GH administration was too short to stimulate local productions of IGF-I in muscle, which may have caused an increased rate of muscle protein synthesis. Recent studies, however, have not shown any stimulation of muscle protein synthesis by IGF-I in humans 45,46.

[GH by itself in the short-term does not increase muscle protein synthesis. There is evidence that it may do so when its longer-term effect on paracrine IGF-1 is taken into account.

GH leads to two types of IGF-1 creation: endocrine IGF-1 which is created in the liver and circulates systemically and is easy to measure and the autocrine/paracrine IGF-1 which is created in muscle cells and is used therein or in neighboring cells. This latter IGF-1 does not travel systemically but rather exerts its effect locally. Although difficult to measure it is this local IGF-1 which is anabolic in part because it may result in increased muscle protein synthesis.

It is now established that GH and testosterone increase local IGF-1 expression whereas exogenous IGF-1 suppresses local IGF-1 expression. Therefore it is not surprising that systemic IGF-1 fails in increasing muscle protein synthesis]

The Copeland authors 1 suspected “that the increase in muscle mass observed in GH-treated adults 48-51 represents a chronic effect on inhibited proteolysis, mediated by IGF-I.

[So IGF-1 inhibits protein breakdown and GH leads to the creation of IGF-1]

Growth Hormone infusion in traumatized patients accelerates the rates of transmembrane transport of the essential amino acids leucine and phenylalanine 52. The GH-mediated increased ability of transmembrane systems to transport essential amino acids in vivo confirms previous observations in vitro 53,54.

[So while insulin increases transport of a few aminos (alanine & lysine), GH increases amino acid transport for leucine and phenylalanine. This would mean that GH would increase transport of the other aromatic amino acid tyrosine and the other branch-chain amino acids valine and isoleucine]

Besides stimulating whole body protein synthesis, growth hormone suppresses the rate of catabolism of the branched-chain amino acids leucine, isoleucine, and valine 52. This effect has been reported by several other authors using isotopic tracers of leucine at the whole body level 44,55.

[So growth hormone unlike insulin suppresses the breakdown and loss of branch-chain amino acids & probably all amino acids. Thus GH provides more raw materials for insulin-induced higher rate of protein synthesis.]

Glutamine and alanine constitute the major carriers of nitrogen among body tissues 56.In skeletal muscle, these amino acids are constantly being synthesized and released into the bloodstream 52. In severe trauma, alanine release from muscle is greatly accelerated, whereas glutamine release was found to be increased or unchanged 57. The results in the Biolo study 52 indicate that GH administration selectively decreases the rates of synthesis and release of glutamine, whereas alanine synthesis is unchanged during the hormone administration.

[Growth hormone has a negative effect on glutamine synthesis.]

In the Biolo study 52 in their patients, whole body skeletal muscle released 19 g of glutamine per day into the bloodstream before GH administration. After GH administration, glutamine release from skeletal muscle decreased by 50%, whereas at the whole body level, glutamine clearance tended to decrease by 15%.

[So glutamine which is very important to the immune system & is urgently needed in times or severe trauma is not really made available. This in part may be the reason why death occurs in critically ill patients given GH.]

The obvious solution for this potential side effect of growth hormone treatment in critically ill patients is to simultaneously administer exogenous glutamine to offset the decreased availability of the endogenous amino acid.

[This also is a lesson for those seeking muscle anabolism while using GH. Less glutamine is synthesized and thus available in the presence of GH. Thus supplementation with glutamine should increase the potential for anabolism.]
References:

41 – Copeland, K.C., Nair, K.S., Acute growth hormone effects on amino acid and lipid metabolism, Journal of Clinical Endocrinology & Metabolism, 1994 Vol 78, 1040-1047
42 – Horber F, Haymond MW. 1990, Human growth hormone prevents the protein catabolic side effects of prednisone in humans, J Clin Invest. 86~265-272
43 – Fryburg DA, Louard RJ, Gerow KE, Gelfan RA, Barrett EJ. 1992 Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin’s anti-proteolytic action in humans, Diabetes. 41:424-429
44 -Fryburg DA, Barrett EJ. 1993 Growth hormone acutely stimulates skeletal muscle but not whole-body protein synthesis in humans, Metabolism. 42:1223-1227
45 – Turkalj I, Keller U, Ninnis R, Vosmeer S, Stauffacher W. 1992 Effect of increasing doses of recombinant human insulin-like growth factor-I on glucose, lipid, and leucine metabolism in man, J Clin Endocrinol Metab. 75:1186-1191.
46 – Elahi D, McAloon-Dyke M, Fukagwa NK, et al. 1993 Effects of recombinant human IGF-I on glucose and leucine kinetics in man, Am J Physiol. 265:E831-E838.
47 – Yarasheski KE. Campbell JA. Smith K, Rennie MJ, Holloszy JO, Bier DM. Effect of growth hormone and resistance exercise on muscle growth in young men, Am J Physiol 1992;262:E261-7
48 – Jorgensen JOL, Pedersen SA, Thuesen L, et al. 1989 Beneficial effects of growth hormone treatment in GH-deficient adults, Lancet. 1:1221-1225.
49 – Christiansen JS, Jorgensen JOL, Pederson SA, et al. 1990 Effects of growth hormone on bodv composition in adults, Horm Res. 33(Suppl4):61-64.
50 – Christiansen JS, Jorgensen JOL. 1991 Beneficial effects of GH replacement therapy in adults, ACTA Endocrinol (Copenh). 125:7-13
51 – Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. 1991 Growth hormone treatment in growth-hormone deficient adults. I. Effects on muscle mass and strength, J Appl Physiol. 70:688-694
52 – Biolo G. et al., Growth hormone decreases muscle glutamine production and stimulates protein synthesis in hypercatabolic patients, Am J Physiol Endocrinol Metab 279: E323–E332, 2000 53 – Jefferson LS, Schworer CM, and Tolman EL, Growth hormone stimulation of amino acid transport and utilization by the perfused rat liver, J Biol Chem 250: 197–204, 1975
54 – Kostyo JL, Rapid effects of growth hormone on amino acid transport and protein synthesis, Ann NY Acad Sci 148: 389–407, 1968
55 – Carli F, Webster JD, and Halliday D., Growth hormone modulates amino acid oxidation in the surgical patients: leucine kinetics during the fasted and fed state using moderate nitrogenous and caloric diet and recombinant human growth hormone, Metabolism 46: 23–28, 1997
56 – Biolo G, Fleming RYD, Maggi SP, and Wolfe RR, Transmembrane transport and intracellular kinetics of amino acids in human skeletal muscle, Am J Physiol Endocrinol Metab 268: E75–E84, 1995
57 – Biolo G, Toigo G, Ciocchi B, Situlin R, Iscra F, Gullo A, and Guarnieri G., Metabolic response to injury and sepsis: changes in protein metabolism, Nutrition 13: 52S-57S, 1997


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## PRIDE (Feb 17, 2012)

*Amino Acid Pool*

Skeletal Muscle makes up the largest mass of protein in the body and the major reservoir of free amino acids 58. In many circumstances, such as starvation and catabolic states, amino acids are released from muscle into the bloodstream to be utilized in other body tissues 59. At other times circulating amino acids can be actively taken up by muscle when promotion of protein anabolism is needed 59.






Transmembrane transport systems enable the regulation of amino acid exchange between intracellular and vascular compartments.

Muscle hypertrophy results from changes in the rates of protein synthesis and/or breakdown. In addition, an acceleration of the rates of amino acid transport into muscle cells from intracellular pools may contribute to muscle anabolism by increasing amino acid availability for protein synthesis. Studies suggest that muscle protein accretion occurs in the recovery phase after exercise rather than during the actual exercise period. The leucine tracer incorporation technique has shown that the rate of muscle protein synthesis in humans is increased after exercise and remains elevated for greater than 24 hours 60. During that time period the rate of transport of amino acids may play a significant role in determining the overall extent of protein synthesis.

[In addition to the availability of intracellular amino acids, the rate of transport of amino acids in and out of muscle cells plays an important role in determining the extent of net protein synthesis and anabolism. Substrate availability must occur at the site of synthesis and that site resides within muscle cells.]

*Amino Acid Transport*

Under anabolic conditions muscle takes up amino acids from the extracellular amino acid pool in a pattern conforming to the muscle protein composition to be synthesized 61. Skeletal muscles are composed of muscle fibers which contain long cylindrical myofibrils. Many myofibrillar proteins exist as multiple isoforms (variants in amino acid sequence) within the same cell. Muscle development is associated with major changes in the expression of distinct isoforms 62. So while the uptake of amino acids is not arbitrary and follows a specific pattern, this pattern is not fixed but rather is confined to the pattern of amino acid assembly specific to a class of proteins called muscle proteins.

In catabolic states or when protein synthesis is depressed the pattern of amino acid release from muscle does not depend on the muscle’s protein composition and release may appear arbitrary. So for example alanine and glutamine make up at most 15% of muscle protein but have a tendency to account for almost half (50%) of the amino acids released 61. Alanine and glutamine may be synthesized in muscle rather then taken up and this accounts for the disparity.

Several amino acids, leucine, isoleucine, valine, aspartate and glutamate are released in amounts lower then would be expected from their content in muscle protein. Instead they are often catabolized or broken down in muscle and the branch chain amino acids are often converted into a form that may be used in energy processes whereupon they are released into circulation 61. We generalize this process as part of the oxidation process and are concerned primarily with loss of leucine in this manner.

Other amino acids such as glycine, cysteine, serine, threonine, methionine, proline, lysine, arginine, histadine, phenylalanine, tyrosine and tryptophan can be taken up from the extracellular amino acid pool into muscle cells for incorporation into muscle proteins and released via proteolysis (directed intracellular degradation) 61.

The transport of amino acids in and out of muscle cells is carried out by a variety of transporters each primarily capable of only transporting certain types of amino acids based on their chemical makeup. For the most part the thermodynamics of these various transporters determines what class of amino acids they can carry and which factors and hormones may influence their activity 61. For this reason insulin is capable of affecting some transporters while growth hormone is capable of affecting a wider class of transporters.

[The process of substrate availability is not as simple as transport in and out of cells. The rate of transport, synthesis, intracellular degradation and oxidation events all play a role in determining substrate availability. The factors/hormones discussed herein may influence one or more determinants of amino acid availability which necessarily precedes protein synthesis. ]


References:

58 – Waterlow, J. C., Protein Turnover in Mammalian Tissues and in the Whole Body, New York: Elsevier/North-Holland, 1978, p. 117-176
59 – Abumrad, N. N., Interorgan metabolism of amino acids in vivo, Diabetes Metab. Rev. 5: 213-226,1989
60 – Chesley, A., J. D. MacDougall, M. A. Tarnopolsky, S. A. Atkinson, and K. Smith, Changes in human muscle protein synthesis after resistance exercise, J. App. Physiol. 73: 1383- 1388,1992
61 – Zorzano, A., Fandos, C. and Palacin M., Role of plasma membrane transporters in muscle metabolism, Biochem J. (2000) 349 667-688
62 – Epstein, HF and Fischman, DA, Molecular analysis of protein assembly in muscle development, Science 1 March 1991 251: 1039-1044


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## PRIDE (Feb 17, 2012)

*Exercise*

The Biolo study 63 found that after exercise, the rates of both muscle protein turnover and amino acid transport were increased. Protein synthesis and breakdown increased simultaneously but to a different extent. Synthesis increased by 100%, whereas breakdown increased by only 50%. “Consequently, protein balance (synthesis minus breakdown) improved after exercise (becoming not significantly different from zero) but did not shift to a positive value. These results suggest that physical exercise can restrain net muscle protein catabolism but does not directly promote net protein deposition in the post absorptive state. Thus exercise probably needs to interact with other factors, such as feeding, to promote muscle anabolism. 63“

[Having read the wider array of studies on this topic, I can say that the take home message is that exercise reduces catabolism. Exercise increase both breakdown & synthesis of protein but that exercise alone will not tilt things toward anabolism. Amino acid availability is required.]

The notion that increased amino acid availability can directly regulate protein synthesis is further supported by the fact that the rate of synthesis was enhanced during amino acid infusion or in catabolic patients 65, in whom a large primary increase of breakdown occurs. In the present study 65 “therefore the acceleration of protein breakdown and amino acid transport may have contributed to the increase in protein synthesis. Because of the increase in amino acid transport, the changes in protein degradation have been more than offset by the increased rate of synthesis.”

The Gelfand study 65 found that, after exercise, the absolute rate of protein breakdown was accelerated. This catabolic response almost counteracted the increase in protein synthesis.

[So exercise + amino acids = anabolism]

The Biolo study 64 suggests that this mechanism may also be important for amino acid and protein metabolism. Thus physical exercise may not have a direct regulatory effect on the membrane transport systems, but its effect may be due to the increased amino acid delivery to muscle tissue secondary to the increased blood flow.

[The increased uptake in amino acids from exercise was attributed to blood flow]
Anabolism vs. Catabolism

The intracellular availability of amino acids may not be the sole acute regulator of muscle protein synthesis, in as much as hormones and other factors may have direct effects. Nonetheless it seems clear that the rates of breakdown and inward amino acid transport are important factors. The importance of variations in inward transport can be appreciated when the difference between the anabolic response to exercise is compared with the catabolic response to critical illness. In both circumstances, the rate of breakdown is increased 64, 66, but in the case of critical illness, inward transport is relatively impaired, rather than stimulated. As a consequence, muscle synthesis is not stimulated to the same extent as breakdown, with net catabolism resulting. Thus the increase in inward transport after exercise appears to be an important response that enables synthesis to increase to a greater extent than breakdown.

[Inward transport of amino acids may be the crucial factor in determining whether anabolism or catabolism occurs. Impairment leads to catabolism whereas increased uptake leads to anabolism]
Side Note (skin more important then muscle)67

Thus the stability of muscle mass throughout the day is maintained by alternating phases of catabolism during fasting and anabolism after feeding. This process is necessary to supply liver and gut with amino acids for protein synthesis in the fasting state. Our data 67“suggest that the same mechanism is not involved in the skin, because, after – 20 h of fasting, we did not observe any net loss of essential amino acids from this tissue.” From these results, it appears that maintenance of skin mass is a high metabolic priority, and this may occur, at least in part, at the expense of muscle tissue.
References:

63 – Biolo, Gianni, Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans, Am. J. Physiol. 268 (Endocrinol. Metab. 31): E514-E520, 1995
64 – Biolo, G., S. P. Maggi, R. Y. D. Fleming, D. N. Herndon, and R. R. Wolfe, Relationship between transmembrane amino acid transport and protein kinetics in muscle tissue of severely burned patients, Clin. Nutr. 12: 4, 1993
65 – Gelfand, R. A., M. G. Glickman, P. Castellino, R. J. Louard, and R. A. DeFronzo, Measurement of L-[1-14C]leucine kinetics in splanchnic and leg tissues in humans: effect of infusion, Diabetes 37: 1365-1372, 1988
66 – Wolfe, R. R., Nutrition and metabolism in burns. In: Critical Care: State of the Art, edited by B. Chernow and W. C. Shoemaker, Fullerton, CA: Sot. Crit. Care Med., 1986, vol. 7, p. 19-62
67 – Biolo, G, Gastaldelli, A,Zhang, XJ, Wolfe, RR, Protein synthesis and breakdown in skin and muscle: a leg model of amino acid kinetics, Am J Physiol Endocrinol Metab 267: E467-E474, 1994br>


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## PRIDE (Feb 17, 2012)

*Blood flow*

Over the last decade, evidence has accumulated supporting the hypothesis that blood flow is a major regulator of glucose uptake in skeletal muscle 68.

The results of the Biolo study 69 suggest that variations in blood flow may also affect muscle protein metabolism by increasing transport of free amino acids into cells, which in turn stimulates protein synthesis. This notion is supported by the high correlation between blood flow and fractional synthesis rate (FSR).

“In summary, the results of our study 69 demonstrate that net protein synthesis during amino acid administration can be doubled by previous performance of heavy resistance exercise. Moreover, the data suggest a link between the stimulation of protein synthesis after exercise and an acceleration in amino acid transport. The greater rate of transport after exercise may be due to the increase in blood flow 69.

[So Exercise + increased blood flow + amino acids = increased amino acid transport. Of course this leads to the understanding that aminos need to be in the blood prior to the increased blood flow of exercise.]
References:

68 – Baron, A. D., H. Steinberg, G. Brechtel, and A. Johnson, Skeletal muscle blood flow independently modulates insulinmediated glucose uptake, Am. J. Physiol. 266 (Endocrinol. Metab. 29): E248-E253,1994
69 – Biolo, G, An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein, Am. J. Physiol. 273 (Endocrinol. Metab. 36): El22-E129, 1997


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## PRIDE (Feb 17, 2012)

*Igf-1*

The data available in humans indicate that IGF-I has a mechanism of action similar to insulin on protein metabolism 70-73 because IGF-I administration also reduces the rates of whole-body protein breakdown and synthesis. When compared on a molar basis, the action of IGF-I is about 14 times less potent than that of insulin 73,

There is also the possibility that IGF-I might affect protein metabolism only in selected tissues through a local (paracrine) action. In addition due to its longer half-life IGF-1 could influence whole-body protein metabolism when plasma GH concentrations decline.
References:

70 – Turkalj I. Keller U. Ninnis R, Vosmeer S, Stauffacher W. Effect of increasing doses of recombinant human insulin-like growth factor I on glucose, lipid and leucine metabolism in man, J Clin Endocrinol Metab 1992;75:1186-91
71 – Mauras . Horber FF, Haymond MW. Low dose recombinant human insulin-like growth factor-1 fails to affect protein anabolism but inhibits islet cell secretion in humans, J Clin Endocrinol Metab 1992;75:1192-7
72 – Elhay D. McAloon-Dyke M. Fukagawa NK, Sclater AL, Wong GA. Shannon RP. et al. Effects of recombinant human IGF-1 on glucose and leucine kinetics in men, Am J Physiol 1993:265: E831-8
73 – Giordano M, Castellino P. Carrol CA, DeFronzo RA. Comparison of the effects of human recombinant insulin-like growth factor 1 and insulin on plasma amino acid concentrations and leucine kinetics in humans, Diabetologia 1995:38: 732-8


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## PRIDE (Feb 17, 2012)

*IGF-1/IGF-1 Binding Protein 3 complex*

The major beneficial effect of IGF-1/BP3 determined by the Zdanowicz study 74 appeared to be reduced muscle proteolysis. IGF-1/BP3 significantly reduced net protein degradation rates in muscles from rats. Preservation of muscle weight and protein content paralleled this reduced muscle proteolysis. “In a previous study with highly catabolic muscle from dystrophic hamsters, we reported a 27% decrease in muscle protein degradation rates with rhIGF-1; here with IGF-1/BP3, we report a near 40% decrease. A key component of muscle proteolytic pathways, namely calpain-mediated myofibrillar degradation, was also reduced in rhIGF-1-treated dystrophic mice 74.

[So there is an action that neither GH alone nor insulin effects, namely the reduction in protein degradation/breakdown in muscle. Of course GH increases the amount of IGF-1/IGF-1 Binding Protein 3 complex.]

In humans, IGF-1 administration promoted protein anabolism both by stimulating protein synthesis and by inhibiting protein degradation both in muscle and at the whole body level 75,76.

[So IGF-1 administration both stimulates protein synthesis and inhibits protein degradation in muscle & the entire body. However the reduction in protein degradation in muscle is unique to this hormone as this is not a benefit of GH's sole actions, of insulin's actions or of androgen action.]
References:

74 – Zdanowicz, MM, Effects of Insulin-Like Growth Factor-1/Binding Protein-3 Complex on Muscle Atrophy in Rats, Experimental Biology and Medicine 228:891-897 (2003)
75 – Elahi D, McAloon-Dyke M, Fukagawa NK, Sclater AL, Wong GA, Shannon RP, Minaker KL, Miles JM, Rubenstein AH, Vandepol CJ, Guler H-P, Good WR, Seaman JJ, and Wolfe RR, Effects of recombinant human IGF-I on glucose and leucine kinetics in men, Am J Physiol Endocrinol Metab 265: E831–E838, 1993
76 – Fryburg DA, Insulin-like growth factor I exerts growth hormone and insulin-like actions on human muscle protein metabolism, Am J Physiol Endocrinol Metab 267: E331–E336, 1994


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## PRIDE (Feb 17, 2012)

*Androgens*

Pharmacological doses of androgens increase lean body mass in normal men 77 and muscle size in trained athletes 78. The mechanisms responsible for the anabolic effects of testosterone have been explained by Griggs et al. 79. In a group of healthy volunteers, a 12-week administration of a pharmacological dose of testosterone enanthate increased mixed muscle protein synthesis by 27%, did not significantly affect leucine estimates of the whole-body protein breakdown and synthesis but decreased the rate of leucine oxidation 79.

…androgens promote protein anabolism by sparing amino acids from oxidation and increasing their incorporation into proteins, especially muscle proteins 79.

Thus, part of the effects attributed to androgens, namely the suppression of leucine oxidation 80, 81 and the stimulation of whole-body 81, 85 and muscle 82-84 protein synthesis, might be mediated by GH.

[So androgens suppress amino acid oxidation and increase protein synthesis ...either alone or as a synergistic or complementary action of GH.]
References:

77 – Forbes GB, The effect of anabolic steriods on lean body mass: the dose response curve, Metabolism 1985;34:571-3
78 – Hervey GR, Knibbs AV, Burkinshaw L, Morgan DB, Jones PRM, Chettle DR. et al, Effects of methandienone on the performance and body composition of mean undergoing athletic training, Clin Sci Lond 1981:60:457-61
79 – Griggs RC, Kingston W, Jozefowicz RF. Herr BE, Forbes G, Halliday D., Effect of testosterone on muscle mass and muscle protein synthesis, J Appi Physiol 1989:66:498-503
80 – Horber FF. Haymond MW., Human growth hormone prevents the protein catabolic side effects of prednisone in humans, J Clin Invest 1990:86:265-72 52
81 – Yarasheski KE. Campbell JA. Smith K, Rennie MJ, Holloszy JO, Bier DM., Effect of growth hormone and resistance exercise on muscle growth in young men, Am J Physiol 1992;262:E261-7
82 – Lundeberg S. Beifrage M, Werneman J. von der Deken A, Thunnel S, Vinnars E., Growth hormone improves muscle protein metabolism and whol body nitrogen economy in man during a hyponitrogenous diet, Metabolism 1991:3:315-22
83 – Fryburg DA, Barrett EJ., Growth hormone acutely stimulates skeletal muscle but not whole-body protein synthesis in humans, Metabolism 1993;9:1223-7
84 – Fryburg DA, Gelfand RA. Barrett EJ, Growth hormone actuely stimulates forearm muscle protein synthesis in normal humans, Am J Physiol 1991;260:E499-504
85 – Copeland KC. Nair KS., Acute growth hormone effects on amino acid and lipid metabolism, J Clin Endocrinol Metab 1994: 78:1040-7


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## PRIDE (Feb 17, 2012)

*Thyroid hormones (catabolic NOT anabolic)*

In contrast, both rates of whole-body protein breakdown and synthesis are increased by the administration of T3 and T4 to normal subjects 86. Under these circumstances net protein catabolism occurs because the stimulation of protein synthesis is overcome by a greater stimulation of amino acid oxidation 86.

[Thyroid hormones are catabolic because they stimulate breakdown to a greater extent then synthesis.]

The data on the role played by normal thyroid hormone concentration in the physiological regulation of everyday protein metabolism in normal humans are very limited. In growing rats it has been suggested that thyroid hormones contribute to the increase in protein synthesis induced by meal absorption 87. This does not appear to be the case in humans, according to the evidence that meal-induced changes in protein kinetics occur in the absence of significant changes in the plasma concentrations of T3 and T4 88.

[Thyroid hormones do not appear to contribute to protein synthesis following meals in humans. In rats yes...but not humans. In other words these hormones in normal humans do not add to the protein synthesis that meals induce.]

Basal concentrations of thyroid hormones have differential effects on individual protein kinetics and they play a role in the physiological regulation of protein metabolism of selectively modulating the synthetic or the catabolic rates of target proteins.

[Base levels of thyroid hormones play a general role in modulating both catabolism and synthesis of proteins. Other then restoring abnormalities there doesn't appear to be predictable benefit to manipulating thyroid hormone levels if anabolism is the goal.]
References:

86 – Tauveron I, Charrier S, Champredon C, Bonnet Y, Berry C, Bayle G, et al., Response of leucine metabolism to hyperinsulinemia under amino acid replacement in experimental hyperthyroidism, Am J Physiol 1995;269:E499-507
87 – Jepson MM, Bates PC, Millward DJ., The role of insulin and thyroid hormones in the regulation of muscle growth and protein turnover in response to dietary protein, Br J Nutr 1988;59:397-415
88 – Pacy PJ, Price GM, Halliday D, Quevedo MR, Millward DJ., Nitrogen homeostasis in man: the diurnal responses of protein synthesis and degradation and amino acid oxidation to diets with increasing protein intakes, Clin Sci 1994:86:103-18


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## PRIDE (Feb 17, 2012)

*Catabolism*

*Cortisol, Glucagon, Thyroid hormones*

Thus, whole-body 89 and muscle protein 90 catabolism induced by triple hormonal infusions appear to be mediated by a similar mechanism. The hormones, through the stimulation of protein breakdown, increase the intracellular availability of amino acids; the net catabolic effect results from the fact that hormonal action promotes the oxidative disposal of these amino acids more than their utilization for the synthesis of new proteins.

[These hormones, especially if they are present together promote protein breakdown and rather then making the amino acid pool available for resynthesis, they increase loss by stimulating oxidation.]
References:

89 – Bessey PQ, Waiters JM, Aoki TT, Wilmore DW., Combined hormonal infusion simulates the metabolic response to injury, Ann Surg 1984;200:264-80
90 – Gore DC, Jahoor F, Wolfe RR, Herndon DN., Acute response of human muscle protein to catabolic hormones, Ann Surg 1993:218:679-84


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## PRIDE (Feb 17, 2012)

*Summary*

Notes:

    In the following table Growth Hormones actions are segregated from IGF-1. However GH leads to IGF-1 & Binding Protein creation 6-8 hours later so their actions are collectively bound together.
    The color green is used to indicate a positive effect. The color red is used to indicate a negative effect.


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