Growing Beyond What Nature Intended Part 1

Mechanisms of Action for Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1)

Warning:The following information is intended only as a hypothetical consideration of ways in which human physiology may be altered, through pharmacological means, to achieve striking muscularity. The drugs discussed in this series of articles are, by and large, prescription drugs and should not be used without the supervision of a qualified physician. No attempt should be made to circumvent the laws in your area to obtain these drugs without a prescription. As always, Meso-Rx does not condone in any way the illegal acquisition and/or use of prescription drugs for purposes other than those approved by the FDA or other legally recognized regulatory bodies.

Bodybuilding is a gaudy demonstration of human accomplishment. The attitude that comes with it reminds me of the Baroque cathedrals of Europe where every inch of artistry shouts, “More is better”! At the same time, bodybuilding is a subculture, as well as a science. It is a multi-disciplinarian science including physiology, biology, endocrinology, metabolism, cellular physiology, genetics, molecular biology, and we mustn’t forget, pharmacology. The list of scientific fields pertaining to bodybuilding is extensive.

I view bodybuilding contests as a county fair of sorts. When I ponder the present status of professional bodybuilding I often imagine seeing prize winning cattle being brought before hoards of voyeuristic onlookers, marveling at the spectacle of seeing something beyond what nature intended.

As a bodybuilder I can’t help but think of all the time, energy, food, genetic tinkering and drugs that went into creating such an impressive muscle bound specimen. Here, at the fair, growing prize winning cattle is not a question of morality or ethics, but rather a manifestation of dedication, the proper application of knowledge, and perhaps a display of financial resources. The things done to the animal to make it grow bigger, leaner and faster are, for the most part, seen as beneficial. I hold bodybuilding in the same arena as this. Using drugs, and one day soon genetic tinkering, to grow thehumanbody bigger, leaner, in half the time is not, in and of itself, a question of morality, but rather an exercise in scientific accomplishment. It is an expression of human understanding in the scientific fields heretofore mentioned in order to gain control of the natural world around us, or in this case, within us.

So why is it that bodybuilding fails to be recognized as a legitimate area of scientific inquiry among most peer review scientific journals? The answer is complicated, certainly too philosophical to get into here. For our purposes lets just say that bodybuilding fails to present sufficient value to our society to be officially recognized as something worth devoting time and federal moneys to. In the mean time, scientists will continue to borrow from the tools and practices of bodybuilding to explore their own respective, andrespected, areas of research. We as bodybuilders will have to be satisfied, for the time being, gathering up table scraps from laboratory bench tops to accomplish our goals.

This article will present a holistic picture of some of the most recent scraps to fall our way from the halls of academia. The focus will be on the proper application of human growth hormone (GH) and insulin-like growth factor 1 (IGF-1) for the purpose of building muscle. This information will be presented in such a way as to describe how these growth factors might be incorporated into traditional protocols consisting mainly of androgens. It is important while reading this to remember that my perspective on bodybuilding will undoubtedly effect the way I present this information. I do not in any way condone cheating to win a contest, or breaking state or federal laws to accomplish your goals. Instead, I am simply sharing knowledge with current, or potential, users with appropriate access to anabolic substances.

The GH/IGF-1 Axis

Your body’s GH levels are tightly regulated by numerous chemical messengers including macronutrients, neurotransmitters, and hormones. The signal to increase your body’s GH levels starts in the hypothalamus. There, two peptide hormones act in concert to increase or decrease GH output from the pituitary gland. These hormones are somatostatin (SS) and growth hormone-releasing hormone (GHRH). Somatostatin acts at the pituitary to decrease GH output. GHRH acts at the pituitary to increase GH output. Together these hormones regulate, in pulsatile fashion, the level of GH you have floating around in your body (see Fig. 1).

Several factors can effect this delicate balance. First, GH is subject to negative feedback in response to its own release. GH, as well as IGF-1, circulate back to the hypothalamus and pituitary to increase SS release, thereby decreasing GH release. GH may also act in an autocrine and paracrine (i.e. Effecting the source cells and neighboring cells without having to enter the circulation) fashion within both the hypothalamus and pituitary.

Neurotransmitters also effect GH levels at the hypothalamus. Thisneuroendocrinecontrol is still being elucidated but some factors are already clearly involved (see table 1).

Table 1.

Nutrition and metabolic factors also modulate GH levels. A fall in blood glucose such as during exercise or during sleep causes an increase in GH secretion. High protein feedings increase acute GH secretion. Some amino acids such as L-arginine seem to increase GH by decreasing SS release from the hypothalamus. Even the vitamin Niacin has been shown to increase exercise induced GH release by 300- 600%(Murray, 1995). In this particular study there were four separate trials where 10 subjects cycled at 68% VO2 max for 120 min followed by a timed 3.5-mile performance task. Every 15 min during exercise, subjects ingested 3.5 ml./kg lean body weight of one of four beverages: 1) water placebo (WP), 2) WP + 280 mg nicotinic acid.l-1 (WP + NA), 3) 6% carbohydrate-electrolyte beverage (CE), and 4) CE + NA. Ingestion of nicotinic acid (WP + NA and CE + NA) blunted the rise in free fatty acids (FFA) associated with WP and CE; in fact, nicotinic acid ingestion effectively prevented FFA from rising above rest values. The low FFA levels with nicotinic acid feeding were associated with a 3- to 6-fold increase in concentrations of human growth hormone throughout exercise. The question remains, does this dramatic, yettemporary, increase in GH lead to a greater training effect? It may lead to greater glycogen storage capacity but other than that, we really don’t know.

Caloric restriction dramatically reduces serum levels of IGF-1 yet at the same time increases GH release. This mechanism effectively helps the individual adapt metabolically without having anabolic actions which would potentially hasten death by starvation. It is important to understand that GH can either be anabolic or catabolic. When nutrient intake is high, GH secretion is increased leading also to increased levels of IGF-1, IGFBP3 and insulin. The main role of GH under these conditions is to increase anabolism through local growth factors like IGF-1 and insulin. Conversely, when nutrient intake is low, GH is again increased. But this time there is no concomitant increase in IGF-1, IGFBP3, or insulin. Under these circumstances GH is acting as a catabolic hormone increasing the utilization of fat for fuel thus sparing body glucose yet having no musclebuildingeffects. This behavior of the GH/IGF-1 axis is part of what makes it so difficult to build muscle while dieting. It should be noted that locally produced IGF-1 in skeletal muscle responds normally to training while dieting. This makes heavy poundages a must when trying to get ready for a show without the use of drugs.

Growth Hormone: How does it work?

It is always prudent to have a basic understanding of how a supplement, hormone or drug works to build and/or preserve muscle before considering its use. The knowledge of how a hormone acts in the body is necessary to make your own decisions and manage your own regimens if you plan on utilizing it. Without this understanding you will no doubt end up wasting a lot of money and perhaps put your health at risk.

It has been long believed that GH exerts its anabolic effects on peripheral tissues through IGFs, also known as somatomedins (“mediator of growth”). Binding proteins play an important role in moderating the anabolic effects of both GH and IGF-1. IGF-1 is controlled by at least 6 different binding proteins and there may others waiting to be elucidated. To date there are a couple theories as to just how GH causes growth in target tissues. The first theory is called the somatomedin hypothesis (Daughaday, 1972).

The Somatomedin hypothesis states that GH is released from the pituitary and then travels to the liver and other peripheral tissues where it causes the synthesis and release of IGFs. IGFs got there name because of there structural and functional similarity to proinsulin. This hypothesis dictates that IGFs work asendocrinegrowth factors, meaning that they travel in the blood to the target tissues after being released from cells that produced it, specifically the liver in this case. Indeed, many studies have followed showing that in animals that are GH deficient, systemic IGF-1 infusions lead to normal growth. The effects were similar to those observed after GH administration. Interestingly, additional studies also followed that showed IGF-1 to be greatly inferior as an endocrine growth factor requiring almost 50 times the amount to exert that same effects of GH (Skottner, 1987). Recently rhIGF-1 has become widely more available and is currently approved form the treatment of HIV associated wasting. This increased availability allowed testing of this hypothesis in humans. Studies in human subjects with GH insensitivity (Laron syndrome) has consistently validated the somatomedin hypothesis (Rank, 1995; Savage, 1993).

The second theory as to how GH produces anabolic effects is called the Dual Effector theory (Green, 1985). This theory states that GH itself has anabolic effects on body tissues without the need of IGF-1. This theory has been supported by studies injecting GH directly into growth plates. Further evidence supporting this theory lies in genetically altered strains of mice. When comparing mice who genetically over express GH and mice who over express IGF-1, GH mice are larger. This evidence has been sited by some to support the dual effector theory. Interestingly, when IGF-1 antiserum (it destroys IGF-1) is administered concomitantly with GH, all of the anabolic effects of GH are abolished.

The Somatomedin theory and the Dual Effector theory are not all that different. One simply asserts that GH can produce growth without IGF-1. From the research I am inclined to believe in the Somatomedin theory. This only becomes an issue when one decides whether or not to use just GH or to combine it with IGF-1 or insulin.

From the evidence currently available you can count on three major mechanisms by which GH leads to growth (Spagnoli, 1996).

1. The effects of GH one bone formation and organ growth are mediated by the endocrine action of IGF-1. As stated in the Somatomedin hypothesis, GH, released from the pituitary, causes increased production and release of IGF-1 into the general circulation. IGF-1 then travels to target tissues such as bones, organs, and muscle to cause anabolic effects.
2. GH regulates the activity of IGF-1 by increasing the production of binding proteins (specifically IGFBP-3 and another important protein called the acid-labile subunit) that increase the half-life of IGF-1 from minutes to hours. Circulating proteases then act to break up the binding protein/hormone complex thereby releasing the IGF-1 in a controlled fashion over time. GH may even cause target tissues to produce IGFBP-3 increasing its effectiveness locally.
3. IGF-1 not only has endocrine actions, but also paracrine/autocrine actions in target tissues. This means that as GH travels to my muscles, the muscle cells increase there production of IGF-1. This IGF-1 may then travel to adjacent cells (especially satellite cells) leading to growth and enhanced rejuvenative ability of cells that didn’t see any GH. This is as suggested by the Dual Effector theory.

IGF-1: How does it work?

To understand how IGF-1 works you have to understand how muscles grow. The ability of muscle tissue to constantly regenerate in response to activity makes it unique. It’s ability to respond to physical/mechanical stimuli depends greatly on what are called satellite cells. Satellite cells are muscle precursor cells. You might think of them as “pro-muscle” cells. They are cells that reside on and around muscle cells. These cells sit dormant until called upon by growth factors such as IGF-1. Once this happens these cells divide and genetically change into cells that have nuclei identical to those of muscle cells. These new satellite cells with muscle nuclei are critical if not mandatory to muscle growth.

Without the ability to increase the number of nuclei, a muscle cell will not grow larger and its ability to repair itself is limited. The explanation for this is quite simple. The nucleus of the cell is where all of the blue prints for new muscle come from. The larger the muscle, the more nuclei you need to maintain it. In fact there is a “nuclear to volume” ratio that cannot be overridden. Whenever a muscle grows in response to functional overload there is a positive correlation between the increase in the number of myonuclei and the increase in fiber cross sectional area (CSA).When satellite cells are prohibited from donating new nuclei, overloaded muscle will not grow(Rosenblatt,1992 & 1994; Phelan,1997). So you see, one important key to unnatural muscle growth is the activation of satellite cells by growth factors such as IGF-1.

IGF-1 stimulates both proliferation (an increase in cell number) and differentiation (a conversion to muscle specific nuclei) in an autocrine-paracrine manner, although it induces differentiation to a much greater degree. This is in agreement with the Dual Effector theory. In fact, you can inject a muscle with IGF-1 and it will grow! Studies have shown that , when injected locally, IGF-1 increases satellite cell activity, muscle DNA content, muscle protein content, muscle weight and muscle cross sectional area (Adams,1998).

On the very cutting edge of research scientists are now discovering the signaling pathway by which mechanical stimulation and IGF-1 activity leads to all of the above changes in satellite cells, muscle DNA content, muscle protein content, muscle weight and muscle cross sectional area just outlined above. This research is stemming from studies done to explain cardiac hypertrophy. It involves a muscle enzyme calledcalcineurinwhich is a phosphatase enzyme activated by high intracellular calcium ion concentrations (Dunn, 1999). Note that overloaded muscle is characterized by chronically elevated intracellular calcium ion concentrations. Other recent research has demonstrated that IGF-1 increases intracellular calcium ion concentrations leading to the activation of the signaling pathway, and subsequent muscle fiber hypertrophy (Semsarian, 1999; Musaro, 1999). I am by no means a geneticist so I hesitated even bringing this new research up. In summary the researchers involved in these studies have explained it this way, IGF-1 as well as activated calcineurin, induces expression of the transcription factor GATA-2, which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of the transcription factornuclear factor of activated T cellsor NF-ATc1. Thus, IGF-1 induces calcineurin-mediated signaling and activation of GATA-2, a marker of skeletal muscle hypertrophy, which cooperates with selected NF-ATc isoforms to activate gene expression programs leading to increased contractile protein synthesis and muscle hypertrophy. Did you get all that?

In this the first part of “Growing beyond what nature intended” we have discussed the role, function and interaction of growth hormone and insulin-like growth factor-1 in tissue growth. This is referred to collectively as the GH/IGF-1 axis. We learned that this axis is controlled by negative feedback meaning that GH, after being released, circulates back to the hypothalamus and pituitary to effectively stop further GH release. We learned that circulating IGF-1 has the same inhibiting effect on GH release. We discussedverybriefly the role of neurotransmitters in regulating GH release through growth hormone releasing hormone (GHRH) and somatostatin (SS). We even touched on the nitty gritty details of just how IGF-1 does its magic on muscle cells. I’m afraid I may have disappointed a few of you waiting for the “how to” section of this article. Never fear, in part II you will learn about the effects of these hormones as well as androgens, insulin and thyroid hormones when given, individually and combined, topreviouslyhealthy individuals. I will remind you that this article is not intended to encourage you put your health at risk, or to break the law by acquiring and using these substances illegally.As always, the goal Meso-Rx is not to condone the use of performance enhancing substances, but to educate by providing unbiased information about all aspects of high level sport performance and bodybuilding.

Part II: Role of Androgens on GH Secretion and IGF-1 Sensitivity

Selected References:

Murray R, Bartoli WP, Eddy DE, Horn MK. Physiological and performance responses to nicotinic-acid ingestion during exercise. Med Sci Sports Exerc 1995 Jul;27(7):1057-62

Daughaday WH., Hall K., Raben MS., et al: Somatomedin: A proposed designation for the “sulfation factor” Nature 235:107, 1972

Skottner A., Clark RG., Robinson ICAF., et al: Recombinant human insulin-like growth factor: Testing the Somatomedin hypothesis in hypophysectomized rats. J Endocrinol 112:123 1987

Rank MB., Savage MO., Chatelain PG., et al: Insulin-like growth factor improves height in growth hormone insensitivity: Two year’s result. Horm Res 44:253, 1995

Savage MO., Blum WF., Ranke MB., et al: Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). J Clin Endocrinol Metab 77:1465, 1993

Green H., Morikawa M., Nixon T. A dual effector theory of growth hormone action. Differentiation 29:195, 1985

Spagnoli A, Rosenfeld RG. The mechanisms by which growth hormone brings about growth. The relative contributions of growth hormone and insulin-like growth factors. Endocrinol Metab Clin North Am 1996 Sep;25(3):615-31

Phelan JN, Gonyea WJ. Effect of radiation on satellite cell activity and protein expression in overloaded mammalian skeletal muscle. Anat. Rec. 247:179-188, 1997

Rosenblatt JD, Parry DJ., Gamma irradiation prevents compensatory hypertrophy of overloaded extensor digitorum longus muscle. J. Appl. Physiol. 73:2538-2543, 1992

Rosenblatt JD, Yong D, Parry DJ., Satellite cell activity is required for hypertrophy of overloaded adult rat muscle. Muscle Nerve 17:608-613, 1994

Adams GR, McCue SA., Local infusion of IGF-1 results in skeletal muscle hypertrophy in rats. J. Appl. Physiol. 84(5): 1716-1722, 1998

Dunn SE., Burns JL., & Michel RN. Calcineurin is required for skeletal muscle hypertrophy. J. Biol. Chem. 274(31):21908-21912, 1999

Semsarian C, Wu MJ, Ju YK, Marciniec T, et al. Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signaling pathway. Nature 1999 Aug 5;400 (6744) :576-81

Musaro A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 1999 Aug 5;400(6744):581-5

About the author

Bryan Hypertrophy