Research Update #2

by Hypertrophy

As we approach the new millennium we find the science of building muscle progressing faster than ever before. Long gone are the days of simple trial and error when it comes to building muscle. The modern bodybuilder demands more than just "hear say" if they are to adopt a new training routine or nutritional supplement. This column was created to keep today’s bodybuilder on the cutting edge of scientific research that might benefit them in their quest for body perfection.

 Why bother with Synthol^TM when you can have the REAL thing? IGF-1 steps up to the plate!

Title: Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats.
Researchers: Gregory R. Adams & Samuel A. McCue
Department of Physiology and Biophysics, University of California, Irvine, Ca.
Source: Journal of Applied Physiology 84(5): 1716-1722, 1998

Summary: The present study was undertaken to test the hypothesis that direct IGF-I infusion would result in an increase in muscle DNA as well as in various measurements of muscle size. Either 0.9% saline or nonsystemic doses of recombinant human IGF-I (rhIGF-1) were infused directly into a non-weight-bearing muscle of rats, the tibialis anterior (TA), via a fenestrated catheter attached to a subcutaneous miniosmotic pump. Saline infusion had no effect on the mass, protein content, or DNA content of TA muscles. Local IGF-I infusion had no effect on body or heart weight. The absolute weight of the infused TA muscles was ~9% greater (P < 0.05) than that of the contra-lateral TA muscles. IGF-I infusion resulted in significant increases in the total protein and DNA content of TA muscles (P < 0.05). As a result of these coordinated changes, the DNA-to-protein ratio of the hypertrophied TA was similar to that of the contra-lateral muscles. These results suggest that IGF-I may be acting to directly stimulate processes such as protein synthesis and satellite cell proliferation, which result in skeletal muscle hypertrophy.

Discussion: The details of the mechanisms and pathways by which mechanical stress stimulates localized muscle fiber hypertrophy are still being elucidated. It is clear however, that growth hormone (GH), fibroblast growth factors (FGF) and insulin-like growth factors (IGF) play a central role in this process. Insulin-like growth factor I (IGF-I) peptide levels have been shown to increase in overloaded skeletal muscles (G. R. Adams and F. Haddad. J. Appl. Physiol. 81: 2509-2516, 1996). In that study, there was an increase in IGF-1 content before measurable increases in muscle protein and was correlated with an increase in muscle DNA content. Several other studies have shown that muscle fibers undergoing hypertrophy, due to mechanical stress, express elevated levels of IGF-I prior to hypertrophy.

IGF-1 appears to be an important regulator of the nuclear to cytoplasmic ratio. Studies have show that a muscle will only undergo hypertrophy if it can maintain the ratio of the cell’s volume to the number of nuclei within a finite limit. In the study above, a relatively "unloaded" muscle, the anterior tibialis, was injection with 0.9 - 1.9 micrograms/kg/day of rhIGF-1 which then mimicked the effects of physically loading the muscle. There was an increase in protein content, cross sectional area and DNA content. The increase in muscle DNA is presumed to be a result of increased proliferation and differentiation of satellite cells which donate their nuclei upon fusion with damaged or hypertrophying muscle cells. Take note that the quantities of IGF-1 used in the injections were extremely small, much smaller than studies that have shown relatively poor results from administering IGF-1 systemically which range from 1.0 to 6.9 milligrams/kg/day.

All of the attention and discussion of half-hazzardly injecting fat into muscles to increase the girth of a limb is only a symptom of the obsessive nature of bodybuilding. I would imagine that locally injecting minute amounts (micrograms) of rhIGF-1 to actually increase the growth of individual muscles would be a far better alternative to injecting fat, Esiclene or even getting silicone implants. Those bodybuilders at the national or professional level with lagging calves would be wise to consider the results of this study should they stumble across a bottle of Genentech’s rhIGF-1!

Title: Ginsenoside-Rg1 down regulates glucocorticoid receptor and displays synergistic effects with cAMP.
Researchers: Chung E., Kwang YL., Young JL., Yong HL, Seung KL.
Source: Steroids 63:421-424, July/August 1998

Summary: Ginsenoside-Rg1 (G-Rg1) from the roots of Panax ginseng has been shown to bind to the glucocorticoid receptor (GR). To further explore the effect of G-Rg1 binding to GR, a luciferase reporter gene containing two copies of a glucocorticoid response element was constructed and transiently transfected into FTO2B rat hepatoma cells. A dose-dependent induction of the reporter gene was observed in response to G-Rg1, and the inductive effect was blocked by treatment with the antiglucocorticoid RU486. In addition, both G-Rg1- and dexamethasone (Dex)-induced transcription was synergistically enhanced by the treatment of dibutyryl cAMP (Bt2-cAMP). G-Rg1 treatment also led to the down-regulation of intracellular GR content, which was similar to the effect of Dex. By showing that G-Rg1 down-regulates GR and induces GR-mediated transcription synergistically with cAMP, we conclude that G-Rg1 is a functional GR ligand in FTO2B cells.

Discussion: Panax Ginseng is a medicinal plant originating in Asia. It has long been touted as an "adaptogen" or an herb that helps the body cope with stress. In modern times it is marketed as being useful for treating everything under the sun. The mechanisms by which P. ginseng exerts its glucocorticoid-like effects are only now being brought out in the open after centuries of prescribed use.

Glucocorticoids, secreted by the adrenal cortex, can act to suppress the activity of the immune system and inflamation. They are thought to exert their effects through inhibition of lymphokines. Interleukin-1, a lymphokine, has been shown to stimulate adrenocorticotropic hormone (ACTH) which then stimulates the secretion of glucocorticoids such as cortisol. Glucocorticoids then act to suppress further secretion of interleukin-1. In this manner (negative feedback), cortisol acts to reduce the immune response, including inflamation. Glucocorticoids such as cortisone are often used in the treatment of inflammatory disorders and to help the body accept transplanted organs after surgery.

P. ginseng is known to contain active saponins which are phytochemicals possessing the ability to elicit a variety of effects within the human body. Among those isolated from P. ginseng is ginsenoside-Rg1 (G-Rg1). This saponin is found only in trace amounts in the raw herb. In this study it was isolated and put into medium containing isolated hepatoma cells from rats. These cells were transfected with a gene response element known to be activated by ligand binding of the Glucocorticoid receptor. Along with G-Rg1, some cells were also exposed to dexamethasone. Dexamethasone, or Dex, is a synthetic analog of naturally occurring glucocorticoids hydrocortisone, and cortisol. Dex is used clinically in place of cortisone or cortisol for its anti-inflammatory properties as well as for its lack of sodium retaining, or water retaining effects. Dex is a potent ligand for the glucocorticoid receptor.

In this experiment G-Rg1, the ginseng extract, did indeed bind to the glucocorticoid receptor (GR) manifest by increased luciferase activity. In fact, it bound with sufficient affinity to effectively down regulate the number of GRs on the cell surface. Now skeletal muscle is the obvious place any bodybuilder would like to down regulate cortisol receptors. Could it be that one might supplement P. ginseng during cutting cycles in order to down regulate cortisol receptors for the following growth cycle?

Because G-Rg1 is found in only trace amounts in raw ginseng, it may be necessary to take the maximum amount in order to have an effect on cortisol receptors. The "maximum amount" is somewhat ambiguous and caution should be used whenever using herbal products. Keep in mind that while using ginseng you might expect increased glucocorticoid effects such as weight loss and perhaps some water retention. Because cortisol is a potent lipolytic hormone it would only enhance the effectiveness of the cutting cycle.

One interesting finding in this study was the effect of cAMP on the effects of ginseng. cAMP production is stimulated by norepinephrine, a primary lipolytic hormone also released by the adrenal glands, through the second messenger system. We are all familiar with the fat mobilizing effects of norepinephrine stimulated by ephedrine. It seems reasonable that the addition of P. ginseng to the popular ephedrine/caffeine/aspirin stack may further potentiate the stack’s effectiveness. The application of phosphatidyl serine during the following growth cycle may increase the contrast in cortisol action between the two cycles by inhibiting exercise induced cortisol release. This sudden drop in cortisol activity may be enough to elicit new gains in muscle size and strength.

I wouldn’t expect miracles from this strategy, nevertheless, any positive alteration in cortisol action may lead to increased muscle gains over time. As Panax ginseng is readily available and relatively inexpensive, it may prove to be a valuable addition to your supplement arsenal.

Title: Effects of Troglitazone on hepatic and peripheral insulin resistance induced by growth hormone excess in rats.
Researchers: mm,Sugimoto M, Takeda N, Nakashima K, Okumura S, Takami K, Yoshino K, Hattori J, Ishimori M, Takami R, Sasaki A, Yasuda K
Third Department of Internal Medicine, Gifu University School of Medicine, Japan.
Source: Metabolism 1998 Jul;47(7):783-787

Summary: The purpose of the present study was to clarify whether troglitazone, a new insulin-sensitizing drug of the thiazolidinedione class, counteracts the insulin antagonistic effects of recombinant human (rh) GH on glucose metabolism in rats. Male Wistar rats weighing 184 to 226 g were treated either with rhGH (n = 8) or rhGH plus troglitazone (n = 8). rhGH (20 IU/kg body weight/d) was given by subcutaneous injection twice daily for 2 days. Troglitazone was given at 100 mg/kg/d orally for 5 days before and 2 days during rhGH. Saline was injected to the control rats (n = 7). Euglycemic clamp studies with an insulin infusion rate of 8 mU/kg/min were performed in these rats after an overnight fast. Hepatic glucose output (HGO), glucose infusion rate (GIR), and glucose disappearance rate (GDR) were measured. Fasting levels of plasma glucose (6.6 +/- 0.1, 6.1 +/- 0.3, 6.5 +/- 0.2 mmol/L), insulin (187.5 +/- 24.1, 206.4 +/- 24.1, 182.3 +/- 31.0 pmol/L), and serum free fatty acid (FFA) (1.58 +/- 0.18, 1.43 +/- 0.16, 1.61 +/- 0.25 mEq/L) were comparable among rats treated with rhGH, rhGH plus troglitazone, and controls, respectively. Basal HGO was also comparable among the three treatment groups. HGO was suppressed significantly during the hyperinsulinaemic glucose clamp in control rats, but not in rhGH rats. When troglitazone was coadministered with rhGH, suppressibility of HGO during the glucose clamp was comparable to that of controls. GIR (13.5 +/- 4.5 v 24.1 +/- 4.1 mg/kg/min) and GDR (18.1 +/- 5.8 v 30.3 +/- 5.2 mg/kg/min) were decreased by rhGH treatment compared with control values. They returned to normal levels in rats treated with both rhGH and troglitazone (GIR, 22.4 +/- 5.9; GDR, 24.7 +/- 7.1). From these results, it is evident that rhGH treatment impaired insulin's ability to suppress HGO and stimulate peripheral glucose utilization. Troglitazone could block the insulin antagonistic effects of GH on hepatic glucose output and peripheral glucose utilization.

Discussion: The use of Growth hormone for growth hormone deficiency syndrome (GHd) has been practiced since 1958. Up until 1985, all growth hormone preparations came from pituitary extractions. In 1985 a case of Creutzfeld-Jacob disease was reported to have been caused by contaminated growth hormone administration. Since that time, 28 more cases of Creutzfeld-Jacob disease have been reported as a result of contaminated pituitary extract growth hormone administration. Since 1985, recombinant human growth hormone has been produced. This has greatly increased the availability and use of this hormone by non-GH deficient individuals. Everyone from life extensionists to bodybuilders have been using it to effectively change body composition and increase lean mass.

To date, recombinant human GH treatment in patients with or without GHD has produced relatively few side effects, however, glucose intolerance, postprandial hyperglycaemia, and insulin resistance are well known side effects of GH treatment in both animals and humans. GH has been shown to reduce peripheral glucose uptake and prevent insulin mediated decreases in hepatic (liver) glucose output. The majority of studies also indicate that GH administration can cause hyperinsulinaemia (elevated insulin levels). The long term effects on glucose metabolism from GH administration in non-GH deficient adults is not known.

Troglitazone is a thiazolidinedione derivative. It is an antidiabetic drug known to improve glucose metabolism. The mechanism by which troglitazone exerts its antihyperglycaemic effects have been suggested to involve almost every step in the insulin signaling pathway, including insulin receptor kinase, insulin receptor substrate-1, phosphatidylinositol 3-kinase, and glucose transporters.

In the study above we see that coadministration of GH and troglitazone prevented any disturbances in glucose metabolism. Troglitazone therapy began 5 days before GH administration. This is because a lag period of up to 2 - 3 weeks has been reported to be necessary to see the full effects of the drug. Also of interest was the fact that coadministration of thiazolidinediones have been shown not to interfere with the growth promoting effects of GH therapy.

From the results of this study one may assume that coadministration of troglitazone and GH is preferable to GH alone. This strategy may turn out to be a necessary preventative measure taken by non-GH deficient adults using GH to minimize the short term and possible long term deleterious alterations in glucose metabolism. It may also serve as an alternative to using insulin with GH. Because GH can cause hyperinsulinaemia, taking additional insulin only worsens the effects of GH on insulin status. Hyperinsulinemia has been linked to the development of coronary heart disease and type-II diabetes. Anyone using androgens may already be susceptible to coronary heart disease due to altered blood lipid profiles. Adding insulin and GH only increases their risk of heart problems down the road.