CATEGORY: biology/metabolism
TECHNICAL: ****
SUMMARY:
This is a fairly technical document that describes the
different types of fuel the body will use under variable exercise
conditions. Some of you out there, with a background in medicine,
will probably really enjoy the detail -- for others it's a pretty
hard read. As a result, I'm going to summarize some of the more
important (and interesting) points.

* ATP is the body's only energy source, everything is converted
into ATP at some point

* the order of fuels used by the body under intense exercise
conditions is: ATP first, CP second, muscle glycogen, blood
glucose, and liver glycogen. (glucose and glycogen are the
body's sugar reserves). If all of those resources are
exhausted, amino acids (proteins) are then converted to glucose

* "feeling the burn" in a particular muscle implies that the
glucose or stored glycogen are being metabolized at a rate
too fast for the amount of oxygen present. This leads to
lactic acid (causing the burn) which can be carried back to
the liver where it can be re-converted into glucose.
(so it's sort of a self feeding cycle)

* carbohydrate loading can, in general, double the amount of
glycogen stored in the muscle and liver. (and hence improve
your stamina and performance)

* adrenaline and noradrenaline are mostly responsible for the
release of stored glycogen from the liver, and stored free fatty
acids from adipose. Hence, without these two, you won't
be able to tap your body fat for fuel. Fortunately, exercise
increases both of them.

* the body stores fats inside active muscle cells too. This
intra-muscular triglyceride can also be tapped as an energy
source, but they are hit less and less as the intensity
and duration of an exercise increases.

* Proteins and ketones can be used as exercise substrate (fuel)
as well, but they only account for a small percentage, and
aren't very efficient at the task.

* Fats and triglycerides compose a significantly larger percentage
of your body's stored energy reserves. ATP/CP can only last
for a few seconds, and glucose/glycogen reserves can be
depeleted in only a few hours with the right kind of effort.

-------------------------------------------------------------

Basic Exercise Fuel Metabolism (1,2,3)

Introduction

The energy to fuel exercise can be generated from many different
sources. Which source provides the majority of energy during exercise is
dependent on a host of factors (such as availability, intensity/duration
of exercise, etc) all of which will be discussed in later sections. To
provide adequate background for upcoming sections, it will be helpful to
discuss the basics of energy generation first as well as the basic
pathways of fuel utilization during exercise.

ATP: the master chemical

ATP is the only substrate which the body can use for the
generation of energy. Hence, all energy generating pathways have as
their ultimate goal the generation of ATP. When a muscle contracts, ATP
provides energy by being broken down to Adenosine Diphosphate (ADP) in
the following reaction with the help of an enzyme called an ATPase.

ATPase
ATP ------------> ADP + Pi + energy (Note: Pi represents an inorganic
phosphate molecule)

Within each muscle, there is about 6 seconds worth of ATP stored
which can be used for immediate energy. So for activity to continue past
6 seconds, ATP must be generated through various other reactions. The
first of these of these is through what is called the creatine phosphate
(CP) system.

The creatine phosphate system

Also stored in the muscle is a substance called Creatine
Phosphate (CP). This provides a phosphate molecule to ADP to regenerate
ATP so that muscular activity can continue. CP donates it's high energy
Phosphate molecule to ADP to regenerate ATP via an enzyme called creatine
kinase in the following reaction.

Creatine
ADP + CP --------------> ATP + Creatine
Kinase

There is enough stored CP in a normal muscle to provide energy
for approximately the first 15-20 seconds of muscular activity at which
time intramuscular CP is depleted (this provides the physiological basis
for creatine loading which will be discussed in depth in the supplement
section). The CP system operates in the absence of oxygen (it is
anaerobic) and can provide energy very quickly during exercise. However,
as with ATP, it's overall capacity to produce energy is low due to the
limited amounts available. Collectively, stored ATP and CP are known as
the ATP-CP or Phosphagen system. However, the total energy yield from
the ATP-CP system is low due to the small amount of ATP and CP available
in the muscle.

As exercise duration exceeds 10-15 seconds, the ability of the
phosphagen system to provide energy decreases and the body must rely on
other fuel sources to generate ATP. One of these is the breakdown of
glucose or glycogen (known as glycolysis or glycogenolysis respectively
although the term glycolysis will be used here generally to refer to the
breakdown of bodily carbohydrate stores). Glycogen is a storage form of
glucose which is present in muscle and the liver. Glucose circulates in
the bloodstream freely and can be taken up into muscles as needed.

Glycolysis

In a normal individual following a mixed diet, total muscle
glycogen stores may comprise 250-350 total grams of carbohydrate with an
additional 15 grams of carbohydrate circulating in the blood. There is
an additional 90-110 grams of glycogen in the liver but it will be
discussed separately below.

During prolonged exercise at 75% of VO2 max to exhaustion (30-60
minutes or so), muscle glycogen stores will be totally depleted. With
depletion of carbohydrate stores (generally accomplished with either
exhaustive exercise or a carbohydrate free diet or some combination of
the two) followed by several days of a high carbohydrate diet, muscle
glycogen stores can be doubled to 700 grams of glycogen or more.

During exercise, glycogen or glucose is broken down to provide ATP in the
following reaction:

glycolytic enzymes
(Aerobic)
Glucose/Glycogen ---------------------------> ATP + Pyruvate -------->
Krebs cycle, liver, etc
(Anaerobic) |
/
Lactate

The breakdown of glucose or glycogen always initially results in
the formation of ATP and pyruvate. But depending on the availability of
oxygen (which is a function of exercise intensity), the pyruvate
generated has one of two major metabolic fates.

If there is not adequate oxygen present (as with high intensity
exercise), glycolysis only provides 2-3 ATP molecules and the resulting
pyruvate is converted to lactate. Lactate is an acid, causing the
burning sensation felt in the muscles during exercise by lowering pH
inside the muscle. This lowering of muscle pH inhibits glycolysis and
may be one cause of fatigue during high intensity exercise.

In the past, lactate was thought of as only a waste product of
glycolysis that caused fatigue. However, it is now recognized that
lactate is another useful fuel substrate both during and after exercise.
Lactate can be used for energy by slow twitch muscle fibers (Type I) as
well as by the heart. Alternately, lactate can diffuse into the
bloodstream, travel to the liver, and be converted to glucose or glycogen
through the process of gluconeogenesis (literally "the making of new
glucose").

Additionally, following exercise, lactate can be regenerated to
muscle glycogen which may have implications for individuals following a
strict ketogenic diet as glycogen availability is the limiting factor in
many types of exercise. Post-workout glycogen resynthesis from lactate
will be discussed in a later section. This pathway of glycogen and
glucose breakdown is known as fast or anaerobic glycolysis.

If there is adequate oxygen present, glyocolysis produces 38-39
molecules of ATP and the resulting pyruvate is oxidized in the
mitochondria to produce more energy through what is known as the Krebs
Cycle. Alternately, the pyruvate may be released into the bloodstream
where it travels to the liver and is converted to glucose (to be released
back into the bloodstream) through the process of gluconeogensis. This
pathway of glucose or glycogen degradation is known as slow or aerobic
glycolysis.

Liver glycogen

In addition to muscle glycogen and freely circulating blood
glucose, liver glycogen can also play a role in energy production during
exercise. The liver stores up 110 grams of glycogen under normal
conditions and, as with muscle glycogen, this can be increased with
carbohydrate loading. In general, the liver is a storage depot of sorts
for the body. Normally, the liver has a slow output of glucose (from
breakdown of liver glycogen) into the bloodstream. In response to the
release of adrenaline and noradrenaline during exercise (see section on
hormonal reponse to exercise), liver glycogen breakdown and release into
the bloodstream is greatly increased to maintain blood sugar levels.

Additionally, glucagon and cortisol levels (which are also
affected by exercise) further influence liver glycogen release into the
bloodstream. Total depletion of liver glycogen will occur with 24 hours
of total fasting but this may only take several hours during prolonged
exercise (or much less for high intensity exercise). When, liver
glycogen is depleted, blood glucose will also drop and the resulting
hypoglycemia may be one cause of fatigue. Additionally, as it pertains
to ketogenic dieters, the depletion of liver glycogen (and subsequent
drop in blood glucose) below a certain level is necessary for the
intiation of ketogenesis.

It should be noted that total bodily glycogen and glucose stores
can only provide approximately 1500 calories of useful energy (this can
be doubled with carbohydrate loading) or enough to run approximately 15
miles. As this is still fairly limited energy wise, the body has several
other sources of fuel that it can utilize during exercise.

Metabolism of free fatty acids (FFA) and intramuscular triglyceride (TG)

The body has two major stores of fats which can be used during
exercise to provide energy. An 70 kg male with 12% bodyfat has
approximately 70,000 calories of useable energy stored in bodyfat and an
additional 1500 calories stored as intramuscular triglyceride. Assuming
you could use 100% fat for fuel, this would be sufficient to run 720
miles. Even the leanest athlete with only 3 lbs. of bodyfat (containing
approximately 1000 calories worth of useable energy) could run 100 miles
if they were able to use fat for fuel. The question of why humans are
unable to utilize 100% fat for fuel during activity is one that many
researchers have asked themselves and is a topic that will be discussed
in more detail later.

Adipose tissue triglyceride metabolism

As stated, bodily stores of adipose tissue contain approximately
70,000 calories of useable energy stored in the form of triglyceride (TG)
which is the combination of three free fatty acids (FFA) and a glycerol
molecule. But, in order for these triglycerides to be used by the muscle
for fuel, they must go through the following steps:

1. Mobilization: in response to specific hormonal signals during
exercise, adipose tissue TG is broken down within the cell to free fatty
acids (FFA's) and glycerol (which is then released into the bloodstream)
via the enzyme Hormone Sensitive Lipase (HSL). HSL activity is the
ultimate determinant of lipid mobilization during exercise. Adrenaline
and noradrenaline (which increase during exercise) stimulates HSL to
release FFA into the bloodstream while insulin (which decreases during
exercise and increases in response to increases in blood glucose)
inhibits HSL activity and release of FFA to be used for energy. Insulin
and the catecholamines (adrenaline and noradrenaline) are the only two
factors which regulate FFA release from the fat cell (refs).

2. Tranport: FFA's enter the bloodstream where they bind to a fatty acid
binding protein (FABP) to travel through the bloodstream where they are
picked up by the muscle.

3. Uptake: The FFA-FABP complex binds at the muscle and is carried into
the mitochondria for oxidation via the enzyme carntine palmityl
transferase (CPT). *Additionally, once ketogenesis is established in the
liver, circulating free fatty acids will be taken up into the liver and
converted to ketones. The issue of post-exercise ketosis will be
discussed in a later section.*

4. Beta-oxidation: in the mitochondria, the FFA is oxidized yielding ATP
and acetyl-Coa. This acetyl-CoA enters the Krebs cycle to produce more
usable energy.

As will be discussed in a later section, each of the above four
steps has been implicated as the rate limiting factor for the utilization
of FFA during exercise. The beta-oxidation of FFA requires oxygen to
occur (it is sometimes referred to as aerobic lipolysis (refs))

On average, one molecule of FFA will yield 129 ATP or more
depending on the length of the FFA that is burned. Thus, compared to
even aerobic glycolysis, fats provide a much greater energy yield.
However, it should be noted that the oxidation of FFA requires more
oxygen than the oxidation of glycogen or glucose. As will be discussed
later, this has implications for ketogenic dieters.

Intramuscular triglyceride (TG) metabolism

As an additional source of energy, there are droplets of
intramuscular triglyceride stored within the muscle proper. Depending on
a host of factors (to be discussed later), this intramuscular TG will be
oxidized in the same manner as blood borne free fatty acids. As they
exist directly within the muscle fiber, they may exist as a more
immediate source of energy during exercise.

In addition to the use of glycogen/glucose and adipose and intramuscular
TG, the body can also use protein and ketones for fuel during activity.

Protein

Under normal circumstances, protein is not used to a great degree
during exercise. Under most circumstances, it may provide 5% or less of
the total energy yield during exercise. However, with glycogen
depletion, protein in the muscle can be used for fuel either by
conversion to glucose in the liver (again, via gluconeogenesis) or by
direct utilization by the working muscle.

Ketones

The oxidation of ketones for fuel is similar to that of free
fatty acids and intramuscular triglyceride. Under certain conditions,
ketones can enter the muscle where they are converted to acetyl-Coa and
enter the Krebs cycle to produce energy. However, even under conditions
of heavy ketosis, ketones rarely provide more than 7-8% of the total
energy yield which is a relatively insignificant amount. A chart
summarizing the amount of energy available from each fuel source appears
below.

Substrate Total bodily stores Useable energy
----------------------------------------------------------------------
Aerobic/Anaerobic
ATP N/A 1.8 kcal

Anaerobic
CP N/A 8.4 kcal

Anaerobic
Glyocgen (muscle) 250 grams 1025 calories

Depends
Glycogen (liver) 110 grams 451 calories

Depends
Blood Glucose 15 grams 62 calories

Depends
Adipose tissue 7,800 grams 71,000 calories Aerobic

Intramuscular TG 161 grams 1,465 calories
Aerobic

Ketones (!) Varies Varies
Aerobic

Protein (#) Varies 24,000

Note: this assumes a 70kg man with 30kg of muscle and 12% bodyfat.
(!) Ketones rarely provide more than 7-8% of total energy yield even in
highly ketotic individuals (#) Protein only provides 5-10% of total
energy yield and is generally not considered as a major source of energy
during exercise.

Summary

The body can produce energy for exercise by the breakdown of many
different substrates. Generally speaking, fuel utilization can be broken
into two general categories:

Anaerobic energy production

direct breakdown of ATP and CP stored within the muscle, which
predominates during the first 15-20 seconds of exercise anaerobic
glycolysis of muscle glycogen or blood glucose which predominates during
the first 30-70 seconds or so of exercise

Aerobic energy production

aerobic glycolysis of glycogen or blood glucose beta oxidation of
free fatty acids and intramuscular triglycerides oxidation of amino
acids: which generally provides very little of the total energy during
exercise oxidation of ketone bodies: which generally provides very little
of the total energy during exercise

The determination of which substrate provides energy during
exercise depends on a host of factors including availability, the
intensity/duration of exercise, the individual's training status and
gender all of which will be discussed in upcoming sections.

References:

1. "Physiology of Sport and Exercise" Jack H. Wilmore and David L.
Costill. Human Kinetics Publishers 1994.

2. "Endurance in Sport" Ed. R.J. Shephard & P.-O. Astrand. Blackwell
Scientific Publishers 1992.

3. "Exercise Physiology: Human Bioenergetics and it's applications"
George A Brooks, Thomas D. Fahey, and Timothy P. White. Mayfield
Publishing Company, 1996.

Lyle McDonald, CSCS

Some chemistry humor: "If you're not part of the solution, you're part
of the precipitate." -- anonymous

:cool: TJ :cool: