By Robbie Durand, M.A.
Senior Web Editor

Liver IGF-1: How Important is it for Muscle Growth?

I have always been amazed at how fast the science of exercise biology is changing the way bodybuilders train. One thing I have realized is that in order to make continual gains and improve, science can be your greatest ally but you must have an open mind. Having an open mind means that you need to be willing to accept new ideas that goes against what traditional bodybuilders have preached as gospel for years. The latest one is liver IGF-1. I remember reading a year ago that one of the main advantages of a low carb diet was that it raised GH and increased liver IGF-1. Anything that increases liver IGF-1 has to be good for bodybuilding right? Well, that's what I thought for years...I thought that since high intensity exercise increases GH, it also increased serum IGF-1 which was a necessity for muscle growth, but recently these last few months I have read a few new breaking science articles that is going against a long held belief that liver IGF-1 is this potent mediator of muscle growth.

Liver IGF-1: Biology

IGF-I (Insulin-Like Growth Factor) was termed "insulin-like," because of its ability to stimulate glucose uptake into fat and muscle cells. IGF-I shares approximately 50% amino acid structure identity with insulin. There were two discoveries of IGF-I and its effects on multiple tissues at the molecular level: The Somatomedin Hypothesis originally stated that most, if not all, of the effects of GH, were mediated by liver derived IGF-I. It became increasing clear that local production of IGF-I acting either in a paracrine (on nearby cells) or autocrine (on the same cell) manner mediated important biological effects. Indeed, many studies have followed showing that in animals that are GH deficient, systemic IGF-I infusions leads to normal growth. The original Somatomedin Hypothesis was then revised into The Dual Effector theory which proposes an alternative view, involving direct effects by GH on peripheral tissues not mediated by IGF-I and indirect effects of GH-stimulated local IGF-I production locally at the tissue level or distant from the site of action. For example, the direct effects of GH are: increasing muscle amino acid uptake resulting in protein synthesis, glucose output from liver (anti-insulin), fat mobilization (anti-insulin), ketogenesis in liver (anti-insulin), and IGF-I release from liver. Unlike insulin, circulating plasma IGF-I concentrations appear to be independent of diurnal variation. Interestingly, IGF-I concentrations in the serum are 1,000 times higher than those of insulin4. Skeletal muscle hypertrophy is mediated at least by three major molecular processes: increased protein synthesis, increased satellite cell activity, and increased gene transcription, with each one of these contributing to a different pathway to muscle hypertrophy. Interestingly, IGF-I influences all of these mechanisms. However, if Liver derived IGF-1 is this mediator of muscle hypertrophy, how come studies examining resistance trained men do not show changes in serum IGF-1 yet they have increase in muscle growth. IGF-1 is a much more powerful growth activator than insulin; IGF-1 activates six times more genes associated with muscle cell development than insulin. This study showed the critical importance of IGF-1 in muscle cell development, growth, and repair10.

Intramuscular IGF-I: The Holy Grail for Muscle Hypertrophy?
The many molecular mechanisms (i.e. myostatin, calcineurin, ect.) for growth remains unclear, however the evidence that growth factors such as IGF-I increase muscle hypertrophy are obvious. In a 2004 study, in response to 10 weeks of resistance exercise training, there was no change in resting plasma IGF-I, yet significant increases in muscle hypertrophy. Thus, by default, local growth (muscle IGF-1) responses in muscle may be more important than circulating factors in contributing to muscle hypertrophy with resistance training5. Remember, young women not using hormonal contraceptives (estrogen) have on average an 80-fold higher median GH levels than men, and women taking oral contraceptives have 117- to 125-fold higher median GH concentrations than men. In addition, women have higher resting IGF-I levels than men. One of the most shocking studies of the year was done by Marcus Bamman and colleagues which was the first to document that maximal eccentric squats (tension overload) contractions increased muscle IGF-I mRNA (i.e. increased mRNA means that there is increased gene activity taking place in muscle) levels and muscle androgen receptor concentration. Interestingly, there was no change in plasma levels of IGF-I or testosterone after the bout of exercise6. Additionally, in rats the over expression of IGF-I in muscle via transgenic rat models (i.e. genetically manipulated mice) are more effective at increasing muscle hypertrophy than exogenous IGF-I administration7. Interestingly, a recent study on rats from the College of Medicine at Pennsylvania State University in Hershey found that inserting IGF-1 pellets in muscle prevented atrophy following experimentally-induced tissue infection. The pellets promoted protein synthesis and decreased protein breakdown, without releasing IGF-1 into the general circulation9.

It's all In the Muscle...
Several other researchers have been published that the gains in strength and size are all related to "intramuscular growth factors" that are independent of peripheral levels of hormones such as IGF-1. In an elegant study in an issue of The Journal of Physiology, researchers directly tested this hypothesis. By virtue of their experimental design, the authors were able to distinguish between the effects of the muscle overload and liver IGF-1 and muscle IGF-1; as a result, they could directly determine the contribution of mechanical loading independently of systemic and external growth factors. The surprise comes when the muscles of the liver IGF-1 deficient mice were challenged with an increased muscle overload. Whereas the prevailing hypothesis would predict a diminished ability to grow, the muscles of the transgenic liver deficient IGF-1 mice grew in response to overload and activated mTOR in muscle to the same extent as controls. This questions just how important liver derived IGF-1 is for muscle growth. The implication is that the activation of mTOR and muscle growth is entirely dictated by the mechanical load the muscle experiences and not from liver IGF-1 production.

Serum Deficient IGF-1Rats still have Increases In Muscle Hypertrophy
The contribution of the GH/IGF-I axis to skeletal muscle adaptations in response to long-term resistance training is not known. If increases in Liver IGF-1 were able to increase muscle hypertrophy why has so many studies using GH by itself which results in large increases in serum IGF been unsuccessful for inducing muscle hypertrophy? Overexpression or exogenous administration of IGF-I in muscle, neither of which alter serum IGF-I, have been shown to increase muscle mass and delay the onset of age-related sarcopenia1-3. These data suggest that circulating IGF-I may not be necessary for the hypertrophic response to overload. In this month's Journal of Experimental Biology and Medicine, researchers examined the importance of liver derived IGF-1 on muscle hypertrophy. They developed a mouse model which was deficient of liver derived IGF-1 yet muscle IGF-1 was fully functional. The researchers wanted to test if liver IGF-1 production was important for muscle hypertrophy in response to muscle overload. One interesting physiological response is that if you knockout liver IGF-1 the body tries to compensate by increasing GH production, so the liver deficient IGF-1 mice had high levels of GH. Prior to exercise and at the end of exercise, the liver deficient IGF-1 mice had an 80-85% reduction in serum IGF-1 compared to normal mice. Interesting at the end of the study, the mass of the quadriceps was increased in liver deficient IGF-1 mice and normal after exercise and there were no differences between the groups. In sum, the researchers concluded that decreased levels of serum IGF-I in liver deficient IGF-1 mice did not diminish weight-lifting performance or muscle growth; therefore, maximal exercise performance is not dependent on normal levels of liver circulating IGF-I 8. Additionally, it appears unlikely that elevated GH contributes to muscle overload growth process since the response of muscle IGF-I to exercise was not greater in the liver-deficient IGF-1 mice, and since GH signaling was inhibited by exercise. In sum, as a bodybuilder I would not get caught up in the diets that raise IGF-1 or being a big believer that serum IGF-1 is this Holy Grail for muscle hypertrophy, because based on the science...its not panning out that way. The studies seem to point to muscle overload stimulating muscle IGF-1 or intramuscular IGF-1 being the more than liver derived IGF-1 as being a key mediator of muscle growth.