IGF-1 - the Insulin-like Growth Factor 1

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.

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 fashion within both the hypothalamus and pituitary. Neurotransmitters also effect GH levels at the hypothalamus. This neuroendocrine control is still being elucidated but some factors are already clearly involved.

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.

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 as endocrine growth 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. 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.

The second theory as to how GH produces anabolic effects is called the Dual Effector theory. 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.

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. 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. 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. 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.

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 called calcineurin which 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. 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 factor nuclear factor of activated T cells or 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 discussed very briefly 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, to previously healthy 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 ******* 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.