April 1, 1999
Volume 2, Number 7
Research Update
by Bryan Haycock MSc., CSCS
bryan@thinkmuscle.com
Please send us your feedback
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.
Clenbuterol sabotages adaptation to training.
Title:
Attenuating the decline in ATP arrests the exercise
training-induced increases in muscle GLUT4 protein and citrate synthase
activity.
Researchers:
Yaspelkis BB 3rd, Castle AL, Ding Z, Ivy JL
Department of Kinesiology, The University of Texas at Austin, 78712,
USA.
Source:
Acta Physiol Scand 1999 Jan;165(1):71-9
Summary:
Thirty-two rats were assigned to one of four groups: control (CON);
exercise training (TR); exercise training + clenbuterol treatment (0.8
mg/kg/day ) (TR + CL) or exercise training + clenbuterol treatment + 2%
beta-guanidinoproprionic acid diet (TR + CL + beta) to examine whether
alterations in the ATP levels within the muscle mediates exercise
training-induced increases in skeletal muscle GLUT4 protein
concentration and citrate synthase activity. Exercise training consisted
of running the rats 5 d week(-1) for 8 weeks on a motor-driven treadmill
(32 m min(-1), 15% grade).
Gastrocnemius GLUT4 protein concentration and citrate synthase
activity were significantly elevated in the TR animals, but these
adaptations were attenuated in the TR + CL animals. Providing beta-GPA
in combination with clenbuterol enabled training to elevate GLUT4
protein concentration and citrate synthase activity, with the increase
in GLUT4 being greater than that observed for the TR animals. Skeletal
muscle ATP levels were reduced in the TR + CL + beta animals while ATP
levels in the TR + CL animals were significantly elevated compared with
CON. An acute 40-min bout of electrical stimulation of the sciatic nerve
was found to lower skeletal muscle ATP levels by approximately 50% and
elevate cAMP levels in all groups. No difference in post-contraction
cAMP levels were observed among groups. However, post-contraction ATP
levels in the TR + CL animals were significantly greater than the other
groups.
Collectively, these findings suggest that exercise training-induced
increases in skeletal muscle GLUT4 protein concentration and citrate
synthase activity are initiated in response to a reduction in the
skeletal muscle ATP concentration.
Discussion:
Adaptation to training involves increased oxidative capacity of muscle
cells along with increases in the muscle’s ability to take up glucose.
Increases in the oxidative capacity of muscle cells are characterized by
increases in Krebs cycle enzymes. Enhanced glucose uptake is
accomplished through increased glucose transporter protein (GLUT 4)
content in the muscle cell.
The primary function of the Krebs cycle (also called TCA Cycle or
Citric Acid Cycle) is to completely oxidize acetyl groups (derived from
the breakdown of glucose, fatty acids, some amino acids, & ketones)
in a way that results in ATP formation. Oxidation of acetyl CoA accounts
for about two thirds of the ATP formation and oxygen consumption in
mammals. Citrate synthase is the enzyme which starts the Krebs
cycle by combining Acetyl CoA and oxaloacetate to form citrate. By
measuring its activity researchers are able to measure increases in
oxidative capacity as a result of exercise training.
Glucose uptake in muscle tissue occurs by facilitated diffusion. The
term "facilitated" refers to the use of proteins, embedded in
the cell membrane, which help the glucose to diffuse across the
membrane. These proteins don’t remain in the cell membrane all the
time, rather, they are translocated to the cell surface when insulin
attaches to its receptor or when muscle contractions occur. The glucose
transporter proteins most sensitive to insulin and muscle contraction
are called GLUT 4 proteins. With exercise training, increased GLUT 4
content within muscle cells increases the muscle’s ability to take up
glucose from the blood both during exercise and in the presents of
insulin. This results in a "nutrient partitioning" (there’s
a term you haven’t heard in a while) effect by increasing the portion
of dietary carbohydrates that are used by the muscles rather than fat
cells.
In the study above it was shown that these adaptations that are
normally seen with exercise training, are blocked when the animals were
on clenbuterol. Clenbuterol, by activating beta receptors, and thus
stimulating adenylate cyclase activity, artificially maintains ATP
levels within the cell. When this happens, there is no increase in GLUT
4 protein content nor is there an increase in citrate synthase activity.
There appears to be a threshold below which ATP concentrations must fall
before your muscles begin long term adaptive changes.
What does all this mean for Clenbuterol users? Well, if you are a
performance athlete stay away from it during the competitive season.
Clen will inhibit the necessary increases in oxidative capacity need for
enhanced athletic performance with training. It will also hamper your
attempts to replenish glycogen stores as quickly as possible after
competitions.
If you are a bodybuilder Clen is probably going to decrease glycogen
storage not only from lower GLUT 4 levels but also from enhanced
glycogenolytic activity. It is wrong to assume that ephedrine would be
any different. Anything that is going to enhance adenylate cyclase
activity such as clenbuterol, ephedrine, or even forskolin, is going to
prevent these adaptive processes in response to exercise training.
Fortunately, metabolic adaptations are not the key to muscle growth.
Nevertheless, increases in oxidative capacity and increased GLUT 4
content are valuable adaptations when trying to train and recover at
ever increasing levels.
Scientists uncover key protein in neuromuscular junction formation.
Source:
Regeneron Pharmaceuticals Inc.
Summary:
Researchers at Regeneron Phamaceuticals Inc. are working on developing a
drug therapy based on the actions of the protein "Agrin".
"What is Agrin" you say? Agrin is a protein released from
nerve terminals that works to signal the formation of neuromuscular
junctions in developing organisms. The way in which the human body forms
these junctions during early development has long been a mystery. Now,
several factors have been identified that play a role in neuromuscular
junction formation, with agrin being a crucial one.
The neuromuscular junction is the point where the nerve meets the
muscle surface. At this junction the nerve is able to initiate a wave of
depolarization that travels over the cell membrane leading to
contraction.
Here is a brief summary of the steps of muscle contraction.
1. The neuron signal (via acetylcholine release) spreads a wave of
depolarization over the membrane of the muscle fiber which travels down
into the interior of the fiber via surface invaginations called
T-tubules.
2. T-tubule depolarization is linked to calcium ion (Ca2+) release
from the sarcoplasmic reticulum
3. The result is a 100 fold increase in calcium ion concentration in
the fiber interior.
4. The calcium ions then bind to a protein (troponin) in a thin
filament, called actin, in the fiber.
5. The binding of Ca2+ allows protein projections on another
filament, called the thick filament or myosin, to bind to actin.
6. When the myosin projections or cross bridges bind to actin, they
pull on it and cause the muscle fiber to shorten.
7. The action of millions of cross bridges in many fibers causes the
overall muscle to shorten.
8. Finally, the energy to make the myosin cross bridges attach to
actin and cause shortening is derived from the hydrolysis of ATP.
This whole process is referred to as "excitation-contraction
coupling". The importance of agrin lies
in the formation, or clustering, of acetylcholine receptors at the cell
surface. Agrin is the signal released by nerve endings that causes the
aggregation of acetylcholine receptors on the surface of the muscle
fiber. Without this cluster of acetylcholine receptors the nerve could
not elicit an action potential sufficient to cause the muscle fiber to
contract.
Researchers for Regeneron have been studying the interaction of agrin
with its receptor called muscle-specific-receptor kinase, or MuSK If
they could come up with a way to enhance or mimic the actions of agrin
they could potentially combat disease states where there is a
deterioration of the neuromuscular junction such as amyotrophic lateral
sclerosis (ALS). ALS is also known as Lou Gehrig's disease. It is a
progressive, fatal neurological disease affecting as many as 20,000
Americans with 5,000 new cases occurring in the United States each year.
The disorder belongs to a class of disorders known as motor neuron
diseases.
It would be interesting to see what role agrin plays in the
neuromuscular changes seen with resistance training. It could be that
agrin is involved in the enhanced neuromuscular performance typically
seen with resistance training. It could be that in the future, these
junctions could be enhanced or even increased in number in order to
increase strength in athletes.
Someone actually funded a study to see what happens to Bodybuilders
when they diet.
Title:
Effect of a precompetition bodybuilding diet and training regimen on
body composition and blood chemistry.
Researchers:
Too D, Wakayama EJ, Locati LL, Landwer GE
Department of Physical Education and Sport, State University New
York, Brockport 14420-2989, USA.
Source:
J Sports Med Phys Fitness 1998 Sep;38(3):245-52
Summary:
One adult male, steroid and drug free, preparing for his first
competition, was studied. Average daily dietary intake consisted of 2263
calories (71% protein, 16% carbohydrate, 13% fats), with a protein
intake of 5.0 gm.kg-1 body mass (BM).
Initial body weight of 76.3 kgf (16% body fat) decreased to 63.4 kgf
(4.4% body fat). Blood samples for electrolytes, TP, Alb, bilirubin,
LDL-C, TG, UA, and amylase were normal. HDL-C levels increased from 65
to 89 mg.dL-1. Decreased glucose levels (< 50 mg.dL-1), indicated
hypoglycemia. Increased Creatine Kinase levels indicated intense
training. Increased inorganic phosphorus from 3.7 to 8.2 mg.dL-1
suggested lactic acidosis. Increased BUN levels from 16 to 53 mg.dL-1
and creatinine from 1.1 to 1.8 mg.dL-1 may be attributed to a high
protein diet. However, heart muscle enzyme (CK-MB) was not elevated.
Discussion:
It isn’t very often that someone puts up some money to see if
bodybuilding diets are as dangerous as the popular press would have you
believe. I have personally spent hours and hours over the years
listening to so called experts warning other health professionals how
dangerous bodybuilding type diets were. It is in situations like these
that you can’t really raise your hand and say anything to the
contrary. After all, there is an auditorium full of Ph.D.s and M.D.s all
in blind agreement with anything said about bodybuilding simply because
they have no personal knowledge to the contrary.
The diet used in this study was obviously chosen by the participant,
not the investigator. The results show a respectable drop in body fat
from ~16% to 4%. Experience using various body composition measurement
techniques tells me that either one of those measurements could be off
by as much as 5%. Nevertheless, I haven’t seen anyone look too smooth
at a true 4%. It would have been interesting to see if alterations in
the macronutrient composition of this diet (i.e. more fat) would effect
loss of lean tissue. All other blood parameters accept for glucose were
normal. This flies in the face of critics complaining about dehydration,
electrolyte imbalances and kidney failure from high protein/low
carbohydrate diets.
The increase in the popularity of bodybuilding over the last ten
years should impact research as some of those young people become
researchers themselves. The fields of exercise physiology are also
growing in popularity which should increase the amount of research
focusing on bodybuilding issues. Until then we will continue with trial
and error along with a little intuition thrown in for good measure.
New form of Growth Hormone need only be injected once or twice per month.
Source:
Alkermes, Inc. http://www.alkermes.com/
Genetech http://www.gene.com/
Alkermes, Inc. and Genentech announced that based on the successful
completion of a multi-center Phase III clinical trial of Nutropin Depot
and the preliminary results, the companies intend to proceed with plans
to submit a New Drug Application (NDA) in early 1999 with the United
States Food and Drug Administration (FDA). Nutropin Depot is a sustained
release formulation of Genentech's somatropin (recombinant human growth
hormone or rhGH) based on Alkermes' ProLease® injectable sustained
release drug delivery system. In the Phase III clinical trial, Nutropin
Depot was administered either once or twice a month.
The Phase III clinical trial was designed to test the safety,
tolerability and efficacy of Nutropin Depot in the treatment of children
with growth hormone deficiency who had not received any previous
treatment with growth hormone. Seventy-four patients were enrolled at
twenty-seven centers in the United States from December 1997 through
March 1998. Two different dosing regimens were evaluated in the study --
both groups receiving the same total dose of Nutropin Depot. In one
group, thirty-six patients received subcutaneous injections of Nutropin
Depot once a month for a six month period. In the second group,
thirty-eight patients received subcutaneous injections of Nutropin Depot
twice a month for a six month period. The primary efficacy endpoint of
the trial was linear growth rate at six months, annualized. All patients
were given the option of continuing treatment with Nutropin Depot at the
completion of the six month study. Nutropin Depot is designed to reduce
the frequency of injections by encapsulating the drug in biodegradable
microspheres (based on Alkermes' ProLease® injectable sustained release
drug delivery system) that, once injected, is intended to slowly release
rhGH over a sustained period of time.
The complete analysis of the data from the study is currently
underway. Final results are expected to be presented at a scientific
meeting in 1999.
Discussion:
The availability of rhGH that need only be injected once or twice per
month offers relief to individuals on growth hormone therapy. Children
will certainly welcome not having to get so many shots. Athletes
juggling multiple injectable "supplements" often feel like
human pin cushions. It is common practice to use GH three to four times
per day in order to mimic endogenous release patterns. This often
causes athletes on heavy cycles to miss out on public or social
activities that make taking timeout for several daily injections
inconvenient to say the least.
Hormone replacement therapy is becoming more and more acceptable
everyday. With the availability of once per month injections, a wider
population of individuals that may benefit for GH injections will have a
new opportunity for this type of treatment. The elderly, who often must
schedule an office visit for hormone therapy, would obviously benefit.
It can be assumed that life extensionists groups will also jump at the
chance to use and distribute this product. It is unlikely that
Nutropin Depot will be any less expensive than other currently available
forms of rhGH.
by Bryan Haycock MSc., CSCS
bryan@thinkmuscle.com
Please send us your feedback
on this article.