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08/18/2004
Muscular Matters
Forget the tsunami that I discussed last week. Nature showed
last week that it doesn’t take a tsunami to wreak havoc over a
widespread area. Fortunately for us, the remnants of Charley
barely touched our part of New Jersey. (We’ve had quite enough
[politically] stormy weather in Jersey this past week.) Happily,
our very good friends in Venice, Florida were similarly
unaffected by Charley although, as we spoke with them on the
phone, we could hear ambulances passing by on their way from
Punta Gorda, where the hospitals were severely damaged. On
the other hand, Charley carved Captiva, one of our favorite spots,
into two islands. Marco Island, from which I’ve written many
columns as a snowbird, escaped Charley’s wrath.
The sunny skies of Greece contrasted sharply with the stormy
scenes in Florida and the Olympic games provided some respite
from the troubling pictures on our TV screens. But there’s a dark
side to the Olympics, not to mention sports in general - doping
by some athletes to enhance their performance. Some sports
reward superior physical endurance while others reward superior
physical strength. The identification of those who use illegal
performance-enhancing drugs is a continuing battle between
those who work to improve detection techniques and those who
tweak the molecular composition of drugs to evade detection.
This battle has become more complex with the advent of “gene
doping”. Take, for example, cross-country skiing, a sport that
requires lots of endurance. Back in the 1964 Olympics, Finnish
cross-country skier Eero Mantyranta won two gold medals. At
the time, there was speculation that he had taken some kind of
drug to improve his endurance. Decades later, researchers have
found that he and members of his family possessed a genetic
mutation. Eero did have an inherent advantage over any
competitors without this mutation.
In a test of endurance, the supply of oxygen is a key factor. Try
running or walking at a pace beyond your normal capability and
you start gasping for breath. The genetic mutation in the
Mantyranta family results in them having much higher than
normal numbers of red blood cells that carry oxygen through the
body. I became acquainted with gene doping and Mantyranta’s
mutation through an article titled “Gene Doping” by H. Lee
Sweeney, chairman of physiology at the University of
Pennsylvania School of Medicine, in the July issue of Scientific
American. Sweeney’s work is also featured in a recent article in
Time magazine. The July 30 issue of Science also had a special
section of six articles on testing human limits in athletics.
It has been known for some time that the kidneys produce a
chemical known as erythropoietin (EPO) that stimulates the
production of red blood cells. The mutated gene in Eero’s family
produces more EPO; hence the increased red blood cell levels.
When EPO became available commercially for doctors to use in
treating anemia, some athletes began using it to raise their red
blood cell counts. Not a good idea! If the dosage and blood
count aren’t monitored carefully, the red blood cell count
becomes so high that the blood becomes like sludge. The heart
has to pump harder to circulate the blood. It would be hard to
come up with a sport that requires more endurance than the
recently completed Tour de France. Doping with EPO is
believed responsible for the deaths of some 20 European cyclists
from heart attacks in the 1980s and even in 1998 a whole team
was disqualified for using EPO.
How do you determine when an athlete is doping with EPO? In
the 1990s, a limit was set on the allowable hemocrit, the
percentage of red blood cells in the blood. That approach wasn’t
satisfactory in that it couldn’t tip off officials if an athlete doped
with EPO to bring the value up to the maximum allowed limit.
For the 2000 Sydney Olympics a combined blood and urine
analysis was introduced. The blood test included measurements
of the hemoglobin and immature red blood cells in the blood.
Here, the taking of blood samples over a period of time would
show up any sudden changes from the norm.
However, it wouldn’t measure EPO use directly. Commercially
produced EPO, known as “recombinant” EPO, is somewhat
different chemically from the naturally produced EPO. Finding
traces of this so-called recombinant EPO in the urine indicates
doping. However, the concentrations are very low and a clever
athlete could cheat by using diuretics to increase urine flow. The
battle between doper and detector continues.
What about the sports that emphasize strength, where muscles
play a key role? Or, more importantly, what about diseases such
as muscular dystrophy that involve severe muscle loss? Sweeney
and others are working on ways to promote muscle growth.
There are three types of muscle in our bodies. One is critical for
sure - cardiac muscle; if our heart’s not working we won’t care
about the rest. The second kind of muscle is smooth muscle,
which lines internal cavities such as the digestive tract. Sweeney
describes the third type, skeletal muscle, as the largest organ in
the body. In a healthy 30-year old, over a third of the body
weight is tied up in skeletal muscle. Over the next 50 years, a
third of that muscle may be lost, especially in relatively
sedentary individuals.
Muscles are complicated bundles of fibers within fibers with
muscle cells ranging up to about a foot in length and with “fast”
fibers for strength and power and “slow” fibers for endurance.
There are built-in shock absorber molecules to protect cell
membranes from damage. Stacks of protein filaments slide
across each other to allow expansion and contraction of the
muscle. Here, let’s concern ourselves with what controls the
growth and loss of muscle. Astronauts in space for extended
periods provide a vivid example of “disuse atrophy” of muscle.
This loss of muscle is not well understood but seems to be the
result of complete shutdown of muscle growth processes while
the programmed cell death process known as apoptosis speeds
up. The body spends a lot of energy keeping up its skeletal
muscle and when the muscles aren’t being used the body thinks,
“Hey, who needs it?” and out it goes. But if we’re very active
and use our muscles, the body recognizes the fact and puts out
signals to certain satellite stem cells outside the muscle fibers to
multiply and add their nuclei into the muscle fibers.
Normally, the body balances the muscle content by pitting a
growth-promoting protein such as the insulinlike growth factor
(e.g., IGF-1) against the growth-inhibiting protein myostatin.
The IGF-1 encourages the satellite cells to multiply while
myostatin tells them to stop multiplying. You may remember
seeing pictures a few years ago of “mighty mice” that had twice
the muscle content of normal mice and didn’t get weaker on
aging. The mighty mice contain an extra copy of a gene that
codes for IGF-1. Sweeney and others are working on
introducing the IGF-1 gene by incorporating it in a harmless
virus that’s injected. Work on mice and rats using this approach
has yielded promising results but human trials are years off.
Direct injection of IGF-1, rather than going through the gene-
virus approach, may already be happening in the athletic arena.
As with the EPO, there will be problems detecting any cheating.
With gene doping, the IGF-1 gene settles in the muscle and the
only way to detect it would be to do a muscle biopsy. Athletes
aren’t going to take too kindly to having pieces of muscle
snipped out before a competition, or anytime for that matter.
These are just a couple examples of substances that have been or
might be used to enhance performance. We’ve discussed the
IGF-1 gene to promote muscle growth; another approach being
studied is to introduce a gene to block myostatin. Remember,
myostatin limits muscle growth. And there are other compounds
involved – muscles are a complex component of our bodies.
What will the future look like? Will children be tested at birth
for mutations favoring athletic prowess? If an Olympic star is
shown to have a natural genetic advantage (like Eero), will
competitors be allowed to dope up to levels that compensate for
their inherent disadvantage? I’m not going to worry about such
things. I’m just going to watch those amazing gymnasts go
through their mind-boggling routines. I can still remember the
sense of achievement I got back in high school gym class when I
managed to do a simple forward roll!
Allen F. Bortrum
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