Work and Energy in Muscles

Why can't I sprint forever?

Silly question? Let us take a look at data from the 1964 summer Olympic games. The
participants were extremely motivated individuals. We can assume that they " gave all
they had" , running as fast as possible while still managing to come to the finish line. What
lies behind the undisputable observation that those competing in short distance races ran
faster than competitors in longer races? Why must we reduce speed if we want to run
long distances over extended time intervals? Even the most motivated athletes are bound
by this simple rule. We can see this in the following graph. Running speed is plotted
against the duration of the race. Competitors running more than 30-40 seconds reduced
their velocity markedly and a continual and gradual decrease occurred after about 2
minutes. Marathon runners ran a little more than half of the speed of sprinters.


The explanation for this phenomena is that while the only direct fuel for muscles is ATP,
we do not " use up" ATP while working. Even extremely hard work does not lower ATP
concentrations by more than about 20 %. Several differing energy sources are used by
working muscles to maintain ATP levels. Phosphocreatine, muscle glycogen, blood
glucose and fatty acids from adipose tissue are those possible energy sources. Let us
look at the striking differences between these.
1
A 100 meter sprint takes less than 10 seconds to complete. During this very short period
the major driving forces are stored high-energy phosphates and anaerobic glycolysis. The
runners can perform almost without breathing, using energy stored as ATP, creatine
phosphate and glycogen (that is, anaerobic metabolism) in the active muscles. In contrast
to long-distance runners, sprinters are often large, very muscular people. Sprinters have a
dominance of so-called fast twitch or anaerobic muscle fibers. Those remarkably high
speeds can only be maintained while stored high-energy phosphate in the form of
phosphocreatine is present. Almost all studies of phosphocreatine metabolism conclude
that stores of phosphocreatine in skeletal muscle are emptied within the first 30 seconds
of strenuous activity. After that, the very rapid rate of running must be reduced. The
energy supply for those who run from about 60 seconds to three minutes is primarily
glycogen stored in muscles and blood glucose. These carbohydrates can be rapidly
oxidized to pyruvate, lactate and CO
2
to provide the ATP required for muscle activity.
However, the rate of ATP synthesis rate is far below that seen when using
phosphocreatine as the phosphate donor. I will soon come back to this.

Metabolism of carbohydrates in muscle.
Energy production, that is ATP synthesis from ADP and P
i
, can occur anaerobically
(without use of oxygen) or aerobically (using mitochondrial reactions and oxygen). Use
of ATP does not lead to major decreases in ATP levels, due to its rapid resynthesis.
Extreme activity leads to no more than a 20% reduction in ATP concentration in muscles.
Anaerobic glycolysis is far more rapid than aerobic metabolism. However, anaerobic
processes can only use stored glycogen or blood sugar as substrates. Neither amino
acids nor fatty acids can be processed without use of oxygen. Muscles differ in their
ability to produce ATP through anaerobic and aerobic reactions. So-called fast-twitch
white muscles with few mitochondria are the " anaerobic" fibers, producing ATP and
yielding lactate acid as a temporary product. Aerobic fibers, those with many
2
mitochondria, produce ATP using carbohydrates, fatty acids and branched-chain amino
acids as substrates. Aerobic glycolysis is a very effective energy production, forming 36-
38 ATP molecules for every glucose which is oxidized to CO
2
and water. However,
aerobic oxidation of all substrates and the linked ATP synthesis are relatively slow
processes. Anaerobic glycolysis provides very rapid formation of ATP for short intervals
while aerobic processes provide energy over longer time intervals. This explains the
differing running rates seen in the example. Sprinters have a dominance of those rapid,
lactate-producing white muscle fibers, while long-distance runners have an abundance of
red oxidative muscle fibers.
Anaerobic ATP synthesis is coupled to formation of lactic acid from stored " glucose"
(actually glycogen) or glucose from the blood (blood sugar). In the next figure you can
see the progress of glucose metabolism following a meal and in a period with little work.
Metabolism of glucose goes two differing ways in this situation. Some of it is oxidized,
generating 2 ATP molecules for each glucose moiety that goes through anaerobic
glycolysis. At the same time, some of the glucose can be stored as the polymeric
anhydride, glycogen, using the energy in an ATP molecule (in the form of UTP) to split out
water from the glucose molecules which form glycogen. We store part of this energy in
the anhydride bond which links glucosyl groups in the glycogen macromolecule. This is
then used later to synthesize phosphorylated glucose (G-1-P) without utilization of ATP.
Glycogen is made and stored at times of glucose excess and under rest or light work. We
use that glycogen to cover future energy expenditures.



3


Breakdown of glycogen occurs when energy demands are increased. We now " get back"
that UTP/ATP that we expended when energy demands were small. We split glycogen with
an enzyme called glycogen phosphorylase. This uses inorganic phosphate to form G-1-P
and G-6-P. Remember, hexokinase required ATP to synthesize G-6-P from glucose. With
glycogen and phosphorylase we can go directly to phosphorylated glucose (G-1-P)
without the use of ATP! Therefore, we now get three ATPs for each glucose equivalent
that goes through anaerobic glycolysis. This is a 50 % increase in energy-winning during
times of need!
This is, of course, in marked contrast to aerobic oxidation where between 36 and 38 ATPs
are formed for every glucose molecule that is oxidized to CO
2
. So, which advantage do we
gain by using anaerobic glycolysis with lactic acid as a temporary end-product? Why do
people burning glycogen anaerobically run faster than those who use aerobic
metabolism? The answer is simply that anaerobic oxidation is exceedingly rapid. Large
quantities of ATP are synthesized during the three minutes or so that this process
dominates muscle metabolism. However, glycogen reserves are rapidly exhausted and
lactic acid accumulation quickly leads to muscle stiffness and pain. Continuing high-
performance work after muscle glycogen is exhausted leads to massive uptake of glucose
from the blood with a resulting fall in blood glucose levels. This leads to central effects,
with a " black out" as the final consequence. Races between 100 and 2000 meters are a
balance between too high and too little energy use; run slowly and lose, run too fast and
pass out!
4
Another way to look at glycogen utilization is to see how this is coupled to work intensity.
Small energy demands do not initiate glycogenolysis, as shown in the figure below.
Lightly loaded muscles manage to cover their energy needs through oxidation of
circulating glucose and fatty acids. However, increasing work loads demands more
powerful contractions and ATP utilization. This increases the rate of glycogen breakdown
to cover these needs. In other words, the harder we work, the sooner we become
exhausted! Reducing the glycogen content of skeletal musculature does not decrease
energy production. It merely shifts the substrate used from glycogen to blood glucose. If
we press our bodies sufficiently, this will reduce blood sugar levels so much that we
begin to lose vision and mental activity. More about this further on.






5
Lactate, energy metabolism's " blind path" .
Why do anaerobically active muscles spew out lactate and pyruvate? Part of the answer
here is that the anaerobic part of glycolysis can proceed much faster than the aerobic
reactions. Thus, pyruvate accumulates because the capacity of the mitochondrial
oxidative reactions is greatly exceeded. But why is that pyruvate converted to lactate?
The key here is that glycolysis is completely dependent on a stable supply a metabolic
oxidant to convert glucose and glycogen to pyruvate. Thus, two molecules of the
nucleotide NAD
+
are converted to NADH + H
+
for each glucose or glycogen molecule that
is oxidized. That is, conversion of 1 glucose to 2 pyruvate molecules requires 2 ADP and 2
NAD
+
( check the figure at the left). So, in order to run anaerobic metabolism while the
substrate is still there, muscles use lactic dehydrogenase to oxidize NADH + H
+
to NAD
+
.
There is no other rapid source for NAD
+
our organs! Production of lactate is not to form an
acid byproduct. If it were not for the need for oxidation of NADH we could just pump out
pyruvate (also an acid, by the way). We do, in fact excrete pyruvate from working
muscles, but the ratio of pyruvate to lactate is determined of the ratio between NAD
+
and
NADH
+
+H
+
. There is much more NAD
+
than NADH
+
in cytosol, so lactate dominates the
picture.
Now, there are two forms of lactate dehydrogenase, so-called isoenzymes. Skeletal
muscle has the M
4
isoenzyme while heart muscle has the H
4
isoenzyme. Liver has a
mixture of these. What is the functional difference between these? Well, both forms of
LDH are inhibited by pyruvate, but the M
4
enzyme is less affected. This allows the M
4
enzyme to form lactate from pyruvate in anaerobically active muscles and keeps the NAD
+

6
production going. In the heart and liver, the H
4
and H
2
M
2
forms may allow more rapid
uptake of lactate which then can serve as a substrate for aerobic energy production.
Whole body lactate metabolism is more complicated than that which is described above.
Click here for a more complete discussion of lactate metabolism.
Aerobic Energy Metabolism
Events that persist for more than roughly three minutes must be powered by aerobic
metabolism. The glucose that goes through anaerobic glycolysis produces pyruvate.
This is then taken up by mitochondria and completely oxidized to CO
2
and water. The total
ATP produced per glucose molecule is over 10 times that produced in anaerobic
metabolism. However, aerobic ATP production is a much slower process than direct
phosphorylation of ADP by phosphocreatine or anaerobic glycolysis. The rate of muscle
activity must be adjusted to the reduced tempo of high-energy phosphate synthesis. This
is summarized in the following table. Here, the rate of synthesis of ATP by exchange with
phosphate in phosphocreatine is set to 100. This is our most rapid ATP-synthesizing
reaction. Anaerobic glycolysis, using glycogen as substrate, is about half as fast.
Another 50% cut can be seen when we examine the rate of aerobic glycolysis starting with
glucose from the circulation. And, once again, there is another 50 % reduction in the rate
of ATP synthesis if we begin with fatty acids from adipocytes.
Physical activity lasting over many minutes and hours cannot be supported by the limited
bodily reserves of glucose and glycogen. Fatty acids from food and adipose tissue,
therefore, supply most of the substrate used by muscle tissue working over time.
Branched-chain amino acids can also serve as substrates for mitochondrial ATP synthesis
in muscle. It is striking that the substrates we have least of are metabolized swiftly, while
those present in large amounts are slowly metabolized. These facts are directly related to
7
the speed at which muscles can operate. Short intervals, high speed, long intervals, low
speed!
Human Energy Stores.
Energy substrates in the human body are either carbohydrates, fat or proteins. Since
energy production from carbohydrates is so much more rapid than that from fat, one
might think that we should accumulate glycogen instead of fat. Nature has chosen fat as
our main energy storage form for two reasons. Firstly, fatty acid are more reduced than
carbohydrates. Therefore, the energy content of fat is over twice that of glycogen and
proteins. Furthermore, both glycogen and proteins are hydrophilic, that is, they bind
water. The result is that stored glycogen and protein have a much lower " energy density"
than the hydrophobic lipids. While fat stores have 9 kcalories per gram wet weight,
carbohydrates and proteins have only 1-1.5 calories per gram wet weight. Our bodies
would have to be very much larger and heavier if we stored large amounts of energy as
glycogen or proteins.
While proteins are not to any great extent burned as an energy-giving substrate in most of
the bodys tissues, they are converted to glucose and can, therefore, support blood sugar
levels and CNS metabolism over long periods. The " skin-and-bone" appearance of
prisoners is clear evidence of the conversion of muscle protein to blood sugar which
holds life in such unfortunates.


8
Consciousness and muscle activity
Muscle activity and running speed is closely coupled to the rate of synthesis of ATP in
muscles. Fuels giving the most rapid rates of energy production are found in limited
amounts. Long-term exercise must be supported through the use of fat as an energy
source. Since lipid metabolism is relatively slow, long-term activities must progress at at
slower rate than high speed short-term activities.
The following figure shows the change in the choice of oxidative substrate during exercise
continuing for several hours. We assume that the person described here starts the work
period eagerly, using stored glycogen at the beginning of the work session. Muscle
glycogen remains the major source of energy during the first half-hour. After this period
we see that fatty acids and blood glucose take over as major energy sources since muscle
glycogen stores have become depleted. Glucose continues as an important energy
source throughout the experimental period. Remember that muscle must have some
degree of anaerobic flux (are always dependent upon some degree of glucose utilization)
and that blood cells and the brain are completely dependent upon glucose as their energy
substrate. Muscle activity over longer periods can reduce blood glucose levels. There is
not more than approximately 20 grams of glucose in blood and extracellular fluids.
Must of the circulating glucose comes from breakdown of liver glycogen and hepatic
gluconeogenesis. Adrenalin, noradrenalin and glucagon activate liver phosphorylase and
initiate glycogenolysis and gluconeogenesis. These same hormones activate hormone-
sensitive lipase in adipose tissue, leading to a gradual increase in the fatty acid
concentration in blood. In the model shown here we see that stabilizing of energy
metabolism in time depends increasingly upon fatty acids as the source of fuel. Blood
glucose utilization rises and falls thereafter to a stable level which is somewhat higher
than that seen at rest. Blood sugar levels remain adequate for brain metabolism so long
as the liver can produce enough glucose to balance that taken up and used in the working
9
muscles. At some point we meet " the wall" (the red line), blood sugar levels decline, we
become dizzy, miss vision and, finally, collapse. Blood sugar levels have fallen below that
needed to maintain CNS activity! This occurs because we are built such that muscle
activity can exceed the rate of hepatic gluconeogenesis. The brain and retina, which are
totally dependent on adequate levels of blood sugar for function, can no longer perform
normally. When blood glucose levels fall below about 2-3mmol/l we lose consciousness
(comatose before being eaten by a tiger?). Recovery does occur, but this takes time:
lactate, amino acids and to some extent glycerol must be converted to glucose to
normalize blood sugar levels.
Note that sudden increases in muscle activity such as spurting to the " finish line" in a
race must be fuelled by anaerobic metabolism (that is, glycolysis from glucose or
glycogen to lactate). This can result in a very rapid uptake of circulating glucose and
quickly lead to a marked fall in the level of blood glucose. The trick in winning races is to
balance carbohydrate " burning" with glucose production. That is, one must work at an
intensity that gives maximal performance without a significant drop in blood sugar level
before the finish. One problem with this is that our daily condition varies; knowing where
today's "wall" is placed is something that we must " feel" .
Muscle Metabolism and Training.
Skeletal muscle accounts for 40-50 % of the normal body weight. These
muscles are comprised of three main fiber types:
Type I Slowly contracting red fibers where aerobic metabolism
dominates.
Type IIA Fibers of intermediate contractility where both anaerobic and
aerobic processes are active.
Type IIB Rapidly contracting white fibers where anaerobic metabolism
is the major energy supply.
The organization of fibers in each of us is determined genetically. People
with a large proportion of type I fibers are not especially fast runners, but
can continue activity longer than those with a dominance of white fibers.
The latter are quicker, but drain their
carbohydrate stores earlier. "Give me a
muscle biopsy and I'll tell you whether
you should be a sprinter or a marathon
runner" is a well-known citation from
sport physiologists. A picture of a
muscle tissue biopsy from a champion
marathon runner, Frank Shorter
(Olympic Gold 1972, Olympic Silver
1976), was recently published in PLoS
Biology 2, 1525-1527:2004. We see that
a majority of the fibers are darkly
stained slow twitch type 1 fibers. These
are rich in mitochondria and have a high
aerobic activity. While these fibers are
"slow" in contraction rate, they can
10
utilize both carbohydrates and lipids for energy production over long time
periods. This is a "typical" muscle fiber distribution for a long-distance
runner. Go to the article for a good review of fiber types and their
contractile and metabolic properties (click here).
If we look at key enzymes in these muscle types we can easily understand
why these differences in function are found. In the first figure we see
enzyme values in "normal" muscles. Two key enzymes from anaerobic
metabolism, hexokinase and phosphofructokinase and two from aerobic
mitochondrial metabolism are shown here (data from Newsholme and
Leech, 1992). The rate-limiting step in glycolysis starting from glycogen is
that catalyzed by phosphofructokinase (PFK). We can clearly see that type
IIA and IIB fibers have a far greater PFK activity than type I fibers. This
permits a rapid glycolysis with formation of ATP and lactate in these fibers
until the substrate is used up. In contrast to this, type I fibers have higher
levels of citrate synthase ( the beginning of aerobic handling of pyruvate)
and of carnitine-palmitoyl transferase, the enzyme which is the starting
point for aerobic metabolism of fatty acids. Note that all of these fiber types
have hexokinase activity and that this is highest in the slow and
intermediate fibers. All types of human skeletal muscle can utilize blood
glucose under stress.
11
Now, perhaps the most interesting part of this story is the effect of training
on the levels of these enzymes. Newsholme led subjects through a vigorous
conditioning period and then took muscle biopsies. The most striking
finding here was that one trained up the aerobic system;
phosphofructokinase activity was relatively unaffected following the
training period. Citrate synthase and carnitine-palmitoyl transferase
activities were approximately doubled in all fiber types. Hexokinase, which
is essential for use of blood sugar, was also markedly increased in both type
I and type IIA fibers.
This coordinates well with previous work showing that training boosts
muscle mass and the capillary bed surrounding the conditioned muscles.
This increases gas exchange and supports the rise in mitochondrial and
oxidative capacity.

"On the move for the sake of science"
The most striking picture of the effects of training on muscle metabolism
that I am aware of can be found in National Geographic, September 2000 in
an article entitled "The Unbeatable Body: Pushing the Limit". A simplified
picture and explanation follow.
12
"On the move for the sake of
science, subjects in a Yale
University fitness study are
measured against each other.
Thirty-seven-year-old Rich (
and 60-year-old Larry (cente
both of whom exercise
regularly, are neck and neck in
cardiovascular fitness. By
comparison, 35-year-old
Salvatore (right) leads a
sedentary life that negatively
affects his cardiovascular and
respiratory fitness. His heart
and major arteries are visibly
smaller, and his VO2maxthe
amount of oxygen his body is
able to useis lower. The brighter colors in his leg show that his muscles
had to work harder to complete an hour on the treadmill *. The point? Our
bodies are programmed to exercise.
left)
r),


Exercise study conducted at Yale University School of Medicine. Study team:
Thomas B. Price, Raynald Bergeron, Jim Rambo, Terry Hickey, Thomas R.
McCauley, Adam Anderson, John C. Gore, and Douglas L. Rothman. Study
subjects shown: Salvatore Iorio, Richard Kennan, and Lawrence W. Rosen".

* The color scale also shows the relative use of aerobic (blue) and anaerobic metabolism
(yellow). Interested readers are urged to go to the original article for insight in muscle
metabolism, blood flow and condition. You can download a more informative version of
this figure from National Geographic by clicking on the thumbnail. Be
patient, the file is large and downloading takes time. Important
physiological data are included in this figure. The men to the left are 37
and 60 years old respectively. Both train daily and completed the one
hour running period on a treadmill. The younger man ran faster and
longer. If you examine the date you will see that the older man had a
reduced vital capacity and iliac artery diameter. These are natural
effects of the aging process. Salvatore, at the right, was only 35 years
old. He was a sedentary worker and followed no training program. His vital capacity and
iliac artery diameter (and presumably blood flow to his legs) were the lowest of these three
men. He walked through the exercise period. We need to be physically active to maintain
good health, strength and the ability to work!
13

" Our bodies are programmed to exercise"
This quote from the article above underlines a major point that has been all to often
forgotten in modern times. Physical condition is dependent upon daily exercise.
Figures from two studies that have emphasized this follow. In the first of these we can see
increasing succinic dehydrogenase and cytochrome c oxidase activity found in biopsies
taken during a 5-week training period. These are key enzymes in the mitochondrial
production of ATP from carbohydrates and lipids. The volunteer's conditioned limbs were
then held more or less inactive during the following 5-week period. The trained muscles
soon lost the conditioning effect of training. Cytochrome c oxidase levels fell below
normal! This emphasizes the fact that daily activity is the best way to keep fit.
Most experts suggest that walking between 30 minutes to a hour daily is necessary for
good fitness and health. Gym visits are fine, but daily activity seems to be even more
important.


14
Another study showing the effects of training on citrate synthase is shown in the next
figure. This is the " entrance" enzyme to aerobic metabolism for both lipids and
carbohydrates. Once again, we can see that training increases enzyme activity and
mitochondrial oxidative capacity. The striking point here is that immobilization reduced
enzyme activity markedly. All of us that have gone with a cast for weeks have experienced
loss of muscle mass and the pronounced weakness that follows and that this figure
indicates.
I may perhaps be accused of overdriving, but once more will I emphasize that the global
surge of overweight with the illnesses that this brings with it is the result of reduced
exercise and training. The urban life style that is being adopted by ever-increasing
numbers is cause of world-wide poor health. Lack of motion leads to muscle weakness
which leads to even less motion...


15
Canadian Indians exercise less too
We can see another example of the effects of modern life on Canadian Indians. These
people live in the Hudson Bay area. There is a film about their modern life made in the late
1920s entitled Nanuk of the North. Even at that time, they were much less active than
previously. The data I have is from 1970-1990. One measured maximal oxygen uptake in
women and men of differing age-groups. As would be expected, capacity decreased with
age, and was larger in men than women. The striking here is that even among these
people who live in a simple but demanding milieu, we find a decrease in physical
condition.
The triangles give values for urban men and women. The men have a vital capacity
approximately identical to that of the 1990 Indian women while the vital capacities of urban
females were significantly lower.
16
There are, in fact, many studies that take up the differing fitness of native and urban
people. Another that I value is shown in the next figure. Here, the authors have looked at
oxygen uptake in native people around the world and compared these values with city
people in differing age groups. The vital capacity of modern urban men was defined as
" average fitness" . Clearly, vital capacity declined among urban people with increasing
f the native
groups fell
under " average
fitness" . Go to
the original
article for
details.


age, with " poor fitness " being characteristic for older city people. None o


hat are the sources of energy in working
uscles?
table. (The
ctional






W
m
Muscle has several possible energy substrates and these are listed in the next
data in the following three tables are from R.W. McGilvery, Biochemistry, a Fun
Approach, W. B. Sa unders, Philadelphia 1970).
17
ATP IS the " currency" of energy metabolism. Muscle contraction, which is coupling
between actin and myosin, is powered by ATP (and ONLY ATP). There is only a small
lager of this material in muscle cells but this is backed up by several buffer systems. The
most rapid of these is the creatine phosphate/creatine phosphokinase system. This is also
the smallest reserve and at maximum utilization it is exhausted in about 4 seconds (newer
data suggests 30 seconds). This is a major source of high-energy phosphate for
sprinters. The next largest energy source is anaerobic glycolysis. Only glycogen stored
in muscles and blood glucose can serve as substrates for anaerobic glycolysis. In
quantity, aerobic glycolysis follows, being able to supply enough energy for muscle
activity over several hours (dependent upon intensity). Fatty acid oxidation has the
largest ATP-producing capacity. This is relatively slow but can produce energy over many
hours if work intensity corresponds to the rate of ATP production. It is fascinating to note
that the most rapid sources of energy are also the most limited. This simple fact underlies
the common observation that running speed falls off with the duration of a race. We can
step up the running rate, exceeding the ATP delivery rate from aerobic metabolism even
when glycogen reserves are used up. Muscle then takes glucose from the blood. The
problem with this is that blood sugar levels then fall and we lose consciousness. To work
at a maximum exertion over time, the load must be in step with aerobic energy production.
We can look at two examples of this, where the work intensity has been adjusted
according to the estimated duration of a race.
A 100 meter sprint is the first case. Here, speed is maximal and the runner has drawn on
his ATP pool, creatine phosphate and glycogen to replenish the high-energy phosphate
used in muscle contraction. This is an extreme example and a decrease in ATP is seen. A
18
prominent observation is that ATP decreased only 20% in spite of the physical effort.
Most of the energy used came from the ATP-buffer systems creatine phosphate/creatine
kinase and anaerobic glycolysis. Around 14 mmoles of glycogen (as glucose) times 3 (3
ATPs from each 6-carbon fragment from glycogen) gave 42 ATP from glycolysis. Eighteen
ATPs came from creatine phosphate.





19
The next example is from an experimental situation which resembles a marathon. Here,
the runner had to keep going for about three hours. The speed in this kind of a race is
quite a bit lower than in a sprint. It is based on aerobic metabolism which gives us a
" slow" but constant flow of ATP production coupled to O
2
reduction. During the first two
hours carbohydrates (blood glucose and glycogen). With time there was a switch in the
substrate utilized. A gradual stimulation of lipolysis led to increases in circulating fatty
acid levels and a concurrent increased use of fatty acids as the substrate for aerobic
metabolism.
To summarize, creatine phosphate and anaerobic glycolysis supply energy for intense,
short work sessions while aerobic metabolism of both carbohydrates and fat supply
energy for longer work sessions. So, if we could just build up creatine phosphate
reserves we really could run fast and forever? No, in spite of many many advertisements
this does not work. Click here if you want to know more about creatine supplements.



The teenage weakling; glycogen storage disease
Clearly, the oxidation of sugar and glycogen in anaerobic metabolism is a very important
contributor to the energy supply of skeletal muscle. Mutations of the enzymes in
glycolysis can inhibit this system. In the following case we will see that reduction in the
20
level of phosphofructokinase, the pace-setting enzyme in glycolysis, leads to muscle
weakness.
" Peter" had a long history of muscle weakness. He was more or less normal while resting,
but experienced severe muscle pain under hard work. The figure shows serum lactate
accumulation during exercise in a control group and in Peter's case. While there was an
abrupt production of lactate in the control group, this was absent in Peter's instance.
Analysis of a muscle biopsy clearly demonstrated that Peter had much higher glycogen,
G-6-P and F-6-P levels than control persons. Furthermore, he had very low levels of
fructose 1,6 bis phosphate. This metabolic " crossover" is indicative of a lack of
phosphofructokinase, the enzyme which catalyses conversion of fructose-6-phosphate to
fructose 1.6 bis phosphate. This enzyme is essential and rate-limiting for ATP production
in anaerobic glycolysis. Peter's case demonstrates the important role of anaerobic
glycolysis. He was unable to utilize muscle glycogen or blood glucose as an energy
source. Here, aerobic oxidation of fatty acids (an almost unlimited but slow process) had
to drive production of skeletal muscle ATP.
The present case presents one of several forms of glycogen storage disease, mainly
affecting skeletal muscle. Other forms affect both liver and/or muscle and can be fatal.


21
Should I Eat More Protein?
The undeniable fact that muscles are very rich in protein has led to a huge
dietary protein supplement industry. A quick internet search gave 74,023
pages with stuff about this. Body-builders and others who desire
impressive bodies eat massive amounts of protein-rich products and amino
acid supplements to support their muscle-building activities. This seems
very logical, but has no basis in well-known facts about protein nutrition.
Arguments about the need for proteins in the diet begin with what we call
nitrogen balance. This is the difference between protein intake (our daily
source of nitrogen-containing compounds) and loss of nitrogen in feces and
urine. Also involved is the large amount of cellular debris and digestive
enzymes which we process in our intestines. As you can see from the
figure, the normal situation is that intake and loss are more or less
equal; nitrogen balance lies at "0". We have no storage form of amino
acids. Synthesis of new protein is supported by the amino acid "pool" in
blood and extracellular fluid. This amounts to around 100g. There are
many studies and reports that have calculated the "dose" of protein needed
to support maintenance of the body under a variety of conditions. One of
the most extensive is from the National Academy Press, Dietary Reference
Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol,
Protein, and Amino Acids (Macronutrients) (2002). Chapter 10 of this
report takes up protein and amino acid metabolism for almost all ages and
22
life conditions. It can be read gratis online but is very long and technical.
The main conclusion is that normal adults require about 0.8-1.0 grams of
dietary protein per kilogram of body weight per day. Adolescent athletes
require most protein and several studies suggest between 1.5 and 2
g/kg/day for this group. Body-builders and some athletes take up to
4g/kg of protein daily. The use of such high protein intake levels is not
medically recommended nor supported. Excessive protein (more than
2g/kg/day) is often associated with dehydration, urinary calcium loss and
inadequate carbohydrate intake. This can lead to weight loss. A summary
of current knowledge can be found in a Medscape article; click here. Amino
acids (and therefore proteins) are not good energy suppliers either.
Muscles can utilize branched-chain amino acids as an energy source, but
they must be transaminated and the amino groups converted to urea in the
liver. This is a slow energy-demanding process. Conversion of amino acids
to glucose has the same disadvantage; formation of urea brakes
gluconeogenesis.
Once again, there is no basis for the enormous protein supplementation
market that has evolved during the past decade! A good, normal diet with a
variable composition gives all the protein that is required for a physically
active life.
23

How do I choose that diet?
Proteins are built up of chains of amino acids that are freed and adsorbed in
the intestine. These are divided into groups; nonessential amino acids that
we can make ourselves and essential amino acids that we cannot synthesize
and must eat. These essential amino acids are present in varying amounts
in body proteins. Therefore, the physiological state of the organism in
question is an important factor in establishing just how "essential" these
different amino acids are. If you look at the following tables you will see
that cysteine is among the non-essential amino acids. We can make it from
serine, also a non-essential amino acid. BUT, we must have methionine, en
essential amino acid, for synthesis of cysteine. Things are not so easy!

The essential amino acids are "essential" according to the situation the
body experiences. Starved rats must have nine different essential amino
acids to gain weight. They do not have to eat the "essential" amino acid
arginine. They have enough arginine in their own "amino acid pool" to build
up their bodies without arginine in their diet in short periods.
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What is "essential" on a daily basis does not necessarily include all of the
amino acids that we cannot produce ourselves. Normal human adults do not
need arginine or histidine in their short-term diet to hold a positive nitrogen
balance.
So, how do you choose a protein source? The problem can be expressed as
"how do I cover my need for essential amino acids? The reason for this is
that every protein we make has a fixed composition. If we have all the
amino acids (building blocks) we need but one, the protein will not be
made! All the pieces have to be available at the right place and the right
time.



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Proteins in food differ in their amino acid makeup. This variation results in
differing "biological" valves as amino acid sources. Food types that have
proteins most like our own are most "valuable". Once again, it is the
essential amino acid content that determines a food's biological value.
Chicken egg protein has a high biological value for humans. In the
following table chicken egg essential amino acid content is set at 1.0. The
biological value of egg protein is 0.94. That is, this protein source gives an
almost perfect mixture of amino acids as a substrate for production of
human proteins. Human milk has just about the same rating. Cow milk has
a somewhat lower methionine and cysteine content; its biological value is,
therefore, a bit lower than chicken egg and human milk. Similarly, beef has
a relative lack of phenylalanine and tyrosine, with a corresponding lower
biological value. The result of this is that one must eat more beef muscle
than chicken egg to obtain the same amount of essential amino acids.
Vegetables and cereals as a group have lower biological values than animal
meat, milk and eggs. We can see that several essential amino acids are less
available here. Vegetarians must eat more protein than meat-eaters to
obtain the amino acids they need for body maintenance.
It is because of this difference in the amino acid composition in food that we
should strive after variation in the daily food source. The recommendation
of around 0.8 gram protein/kg/day takes this into account. Growing and
very active adolescents may have a requirement for double as much protein
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in periods. However, adults do not need more protein than they get in a
normal diet. Increasing physical activity increases appetite and protein
intake is therefore enhanced accordingly. Supplement with large amounts
of protein mixtures and amino acid supplements is unnecessary and can
lead to illness (kidney damage)! There is no medically sound basis for the
enormous "protein supplement" market!
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Bigger and stronger with creatine?
A recent Internet search for creatine supplements yielded over 1,200,000 " hits" . Most of
these are announcements about creatine dietary supplementation aimed to build bigger
and better bodies. What is this all about?
Creatine and creatine phosphate's role in muscle
metabolism.
As I have discussed earlier, all muscle work is powered by ATP. It is the power in the
high-energy gamma bond that drives actin-myosin coupling and muscle contraction. In
spite of this, ATP levels are unusually stable even in working muscles due to several ATP-
buffering systems. Click here to review this.
The creatine phosphate-creatine phosphokinase system is the most rapid of these ATP-
buffering systems. The equilibrium between creatine, creatine phosphate, ADP and ATP is
summarized in the figure to the left. ATP concentration in skeletal muscle lies around 5
mmol/kg while one finds approximately 15-20 mmol/kg of creatine phosphate. Thus small
changes in the ATP/ADP ratio are quickly evened out by use of creatine phosphate.
his has been decisively shown in the human forearm through the use of magnetic
resonance as shown in the next figure. Here we can see the concentrations of inorganic
phosphate, creatine phosphate and the three phosphate groups in ATP. Measurements
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were taken at rest and during a vigorous exercise period. The yellow peaks represent
ATP's phosphate groups. These remain unchanged while exercising while creatine
phosphate levels were markedly reduced (green peak) and inorganic phosphate (red
peak) was markedly increased. (Figure from G. K. Radda, Science 233, 641, 1986 as
presented in Lubert Stryer's Biochemistry)
A logical conclusion might be that, if one could just increase creatine phosphate levels in
muscles, one would be able to carry out more muscle work. The problem with this is that
most studies of the effects of creatine supplementation have not shown enhanced
strength. This is not surprising of several grounds. First, creatine and creatine phosphate
are ionized compounds at physiological pH levels. Accumulation of large amounts of
these in muscle would increase osmolarity and lead to muscle water uptake and swelling.
Secondly, creatine phosphate has an extremely rapid turnover and an eventual increase in
creatine phosphate would be quickly exhausted. Current evidence suggests that creatine
can possibly increase performance lasting for no more than 30 seconds. Creatine
supplementation does not appear to increase muscle mass. Please go to a good review
article by Paddon-Jones et al, " Potential Ergogenic Effects of Arginine and Creatine
Supplementation" Journal of Nutrition 134:2888S-2894S, October 2004 for more
information.
A recent (2007) internet search for " creatine" yielded more than 7,000,000 hits, most of
which concern creatine as a dietary supplement. This in spite of the fact that most studies
have not shown significant effects of creatine on muscle strength. The market for creatine
products is very large. According to Paddon-Jones, creatine sales in the USA alone
exceeded $100 million in 1998. It is tempting to use an earlier comment concerning
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protein dietary supplements: the use of creatine supplements represents " very expensive
urine" !
The bottom line: there is little or no basis for dietary
supplementation with creatine!







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