September, 1998
Volume 1, Number 4
Research Update
by Bryan Haycock MSc., CSCS
bryan@thinkmuscle.com
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on this article.
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 SyntholTM 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!
Ginseng may be useful after all! Looks like Panax Ginseng may posses
the ability to down-regulate cortisol receptors.
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.
Using Growth Hormone? One new drug may make it more effective!
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.
by Bryan Haycock MSc., CSCS
bryan@thinkmuscle.com
Please send us your feedback
on this article.
