Case 1: fuel for the body

What are the different substrates and where are they stored? (structure carbohydrates
and lipids)
Carbohydrates: are stored in the body as glycogen in the muscle and liver. Some glucose is always
present in the blood. Once cells reach their maximum capacity for glycogen storage, excess sugars
convert to and store as fat. This explains how body fat can increase when the diet contains excess
carbohydrates and limited fat.

primarily serve as an energy fuel, particularly during intense physical activity. Energy is derived from
bloodborne glucose (directly from food) and from broken down muscle glycogen. Which powers:

- Contractile elements of muscle

- Central nervous system: this requires an uninterrupted stream of carbohydrates

Lipids: One gram of pure lipid contains about 9 kcal (38 kJ) of energy, more than twice the energy
available to the body from an equal quantity of carbohydrate or protein Fat constitutes the ideal
cellular fuel for three reasons:

- It carries a large quantity of energy per unit weight.

- It transports and stores easily.
- It provides a ready source of energy

Fat is stored in the body as adipose tissue. For young adults, approximately 15% of the body mass of
males and 25% of females consists of fat.
How is energy produced from creatine?
adenosine triphosphate (ATP) Is the direct energy source for cells in the human body. It powers all of
the cell’s energy-requiring processes. the energy donor–energy receiver role of ATP represents the
cells’ two major energy-transforming activities:

1. Extract potential energy from food and conserve it within the bonds of ATP
2. Extract and transfer the chemical energy in ATP to power biologic work

ATP forms from a molecule of adenine and ribose (called adenosine) linked to three phosphates
(triphosphate). The bonds that link the two outermost phosphates (symbolized by “red orange circle”
in the picture below) represent high-energy bonds because they release useful energy during
hydrolysis. The released energy powers body functions including:

- glandular secretion
- digestion
- tissue synthesis
- circulatory function
- muscle action
- nerve transmission
A new compound, adenosine diphosphate (ADP), forms when ATP joins with water, catalyzed by the
enzyme adenosine triphosphatase (ATPase). This reaction cleaves ATP’s outermost phosphate bond to
release an inorganic phosphate ion and approximately 7.3 kcal of free energy, or ∆G (i.e., energy
available for work) per mole of ATP hydrolyzed to ADP. (The symbol ∆G refers to the standard free
energy change measured under laboratory conditions). In the intracellular environment, the value
may actually approach 10 kcal∙mol-1. Yet, the following formula is typically used.

The energy liberated during ATP breakdown directly transfers to other energy-requiring molecules.
Energy from ATP hydrolysis powers all forms of biologic work; thus, ATP constitutes the cell’s “energy
currency.”

ATP splits almost instantly without the need for molecular oxygen. This capability to hydrolyze ATP
without oxygen (anaerobically) generates rapid energy transfer.

- The cell cytosol contains the pathways for ATP production from the anaerobic breakdown of
phosphocreatine (PCr) glucose, glycerol, and the carbon skeletons of some deaminated
amino acids.
- Within the mitochondria, reactive processes harness cellular energy to generate ATP
aerobically the citric acid cycle and respiratory chain—from the catabolism of fatty acids,
pyruvate, and some amino acids
ATP is constantly resynthesized as there is only a very small amount of it present at a time.

Probably not important, but interesting: (A limited ATP supply provides a biologically useful
mechanism to regulate energy metabolism. By maintaining a small amount of ATP, the relative ATP
concentration (and corresponding ADP, Pi , and AMP concentrations) changes rapidly in response to
only a minimal ATP decrease. Any increase in energy requirement immediately disrupts the balance
between ATP and ADP and Pi . The imbalance stimulates the breakdown of other stored energy-
containing compounds to resynthesize ATP. In this way, the beginning of muscular movement rapidly
activates several systems to increase energy transfer.)

Some ATP resynthesis comes directly from the anaerobic splitting of a phosphate from
phosphocreatine (PCr), another intracellular high-energy phosphate compound.
This reaction is stimulated by transient increases in ADP within the muscle’s contractile units during
exercise.

The PCr and ATP molecules share a similar characteristic; a large amount of free energy releases
when the bond cleaves between the PCr’s creatine and phosphate molecules.
Phosphate (P) and creatine (Cr) can rejoin to form PCr. This also applies to ATP: ADP plus P reforms
ATP. Creatine phosphate shuttle
Cells store approximately four to six times more PCr than ATP.
How is energy produced from carbohydrates?
Glycolysis
Happens in the watery medium of the cell outside the mitochondrion. In a sense, glycolysis
represents a more primitive form of rapid energy transfer highly developed in amphibians, reptiles,
fish, and marine mammals. In humans, the cells’ capacity for glycolysis remains crucial during
maximum-effort physical activities for up to about 90 s.

1. ATP acts as a phosphate doner to phosphorylate glucose to glucose 6-phosphate. This traps
the glucose molecule in the cell. This costs energy rather than releasing it. Yet it primes the
glucose molecule for further metabolism.
2. During energy metabolism, glucose 6-phosphate changes to fructose 6-phosphate.
3. The fructose 6-phosphate molecule gains an additional phosphate and changes to fructose
1,6-diphosphate under control of phosphofructokinase (PFK). The activity level of this
enzyme probably limits the rate of glycolysis during maximum-effort activity.
4. Fructose 1,6-diphosphate then splits into two phosphorylated molecules with three carbon
chains (3-phosphoglycerasdehyde); these further decompose to pyruvate in five successive
reactions.

Type 2 muscle fibres contain relatively much PFK, making them more able to produce ATP through
glycolysis under low oxygen conditions.

Three factors regulate glycolysis:

1. Concentrations of the four key glycolytic enzymes: hexokinase, phosphorylase,

phosphofructokinase, and pyruvate kinase
2. Levels of the substrate fructose 1,6-disphosphate
3. Oxygen, which in abundance inhibits glycolysis.
During strenuous physical activity, continued release of anaerobic energy in glycolysis depends on
NAD+ availability to oxidize 3-phosphoglyceraldehyde (step 6)  During rapid anaerobic glycolysis,
NAD+ “frees up” or regenerates when pairs of “excess” nonoxidized hydrogens combine with
pyruvate to form lactate (catalyzed by lactate dehydrogenase)  so pyruvate combines with the H+
to form lactate. This turns NADH + 2 H+ into free NAD+ again.
Lactate is used for ATP production after intense physical activity during recovery when the pace of
activity drops. When sufficient oxygen becomes available during recovery, or when pace slows, NAD+
scavenges hydrogens attached to lactate to form ATP via oxidation  pyruvate is also reformed as H+
is taken away from lactate again (one pyruvate molecule + 2 hydrogens form a molecule of lactate) 
pyruvate can be oxidized aerobically or be turned into glucose in the muscle itself or in the cori cycle.

The anaerobic reactions of glycolysis release only about 5% of the energy within the original glucose
molecule.

Citric acid cycle

Pyruvate enters the mitochondria, its transported by MPC from the cytosol into the mitochondrial
matrix. Extraction of the remaining energy continues when pyruvate irreversibly converts to acetyl-
CoA, a form of acetic acid. This reaction is catalyzed by pyruvate dehydrogenase.

Acetyl-CoA enters the citric acid cycle (Krebs cycle)  Acetyl-CoA gets degraded to CO2 and H+ in the
mitochdria.

The acetyl portion of acetyl-CoA joins with oxaloacetate to form citrate (the same 6-carbon citric
acid compound found in citrus fruits). This reaction is catalyzed by citrate synthase  the original
oxaloacetate then remains after this reaction to react with a new pyruvate molecule.
Enzymes coloured purple are key regulatory enzymes.

The primary function of the citric acid cycle generates electrons (H+) for passage in the respiratory
chain to NAD+ and FAD.
Oxidative phosphorylation
Most energy for phosphorylation derives from the oxidation (“biologic burning”) of dietary
carbohydrate, lipid, and protein macronutrients.

Hydrogen is released from the nutrient substrate during cellular oxidation  this reaction is
catalysed by substrate-specific dehydrogenase enzymes:

- The niacin-containing nicotinamide adenine dinucleotide [NAD+] accepts pairs of electrons

(energy) from hydrogen.  The substrate oxidizes and gives up hydrogens (electrons), NAD+
gains hydrogen and two electrons and reduces to NADH; the other hydrogen appears as H+ in
the cell fluid.
- The riboflavin-containing coenzyme flavin adenine dinucleotide (FAD) serves as another
electron acceptor to oxidize food fragments. Like NAD+, FAD catalyzes dehydrogenation and
accepts electron pairs. Unlike NAD+, FAD becomes FADH2 by accepting both hydrogens.

NADH and FADH2 provide energy-rich molecules because they carry electrons with high energy-
transfer potential.

The cytochromes, a series of iron-protein electron carriers dispersed on the inner membranes of the
mitochondrion, then pass electrons carried by NADH and FADH2. The cytochromes exists in either its
oxidized (ferric or Fe3+ ) or reduced (ferrous, or Fe2+ ) ionic state  By accepting an electron, the
ferric portion of a specific cytochrome reduces to its ferrous form. In turn, ferrous iron donates its
electron to the next cytochrome and so on down the line  electrons are shuttled across the
mitrochondrial membrane  NADH converts back to NAD  During the passage of electrons down
the five cytochrome chain, enough energy releases to rephosphorylate ADP to ATP at three of the
sites. Also one water molecule is formed through H+ electrons to oxygen.
Oxidative phosphorylation synthesizes ATP by transferring electrons from NADH and FADH2 to
oxygen. The picture below illustrates how the energy generated in the reactions of electron transport
pumps protons across the inner mitochondrial membrane into the intermembrane space

Chemiosmosis ATP synthase

Complex 1: accepts H+ from NADH to reduce it to NAD+

Complex 2: accepts H+ from FADH2 to reduce it to it to FAD
The protein complex ATP/ADP translocase exports the newly synthesized ATP molecule. In turn, ADP
and Pi move into the mitochondrion for subsequent synthesis to ATP.

More than 90% of ATP synthesis takes place in the respiratory chain by oxidative reactions coupled
with phosphorylation.

Energy transfer from NADH to ADP to re-form ATP happens at three distinct coupling sites during
electron transport. Oxidation of hydrogen and subsequent phosphorylation occurs as follows:

Cori cycle
The cori cycle removes lactate formed in active muscle and uses it to replenish glycogen reserves that
were depleted during this strenuous activity. Lactate is transported from the production site (active
muscle) towards the liver. Here the lactate undergoes some transformations: lactate  pyruvate 
glucose  glycogen. In this manner glycogen stores can be renewed. You do lose some ATP (-6 ATP in
liver, so net loss -4 ATP as 2ATP is generated in the muscle) in this cycle, so this can not continue
indefinitely.
How much ATP
All ATP formed during glucose metabolism

1. 4 ATP formed during glycolysis, but this process also costs 2 ATP.
2. Four extramitochondrial hydrogens (two NADH) generated in glycolysis yield five ATPs during
oxidative phosphorylation.
3. Four hydrogens (two NADH) released in the mitochondrion when pyruvate degrades to
acetyl-CoA yield five ATPs.
4. Two guanosine triphosphates (GTP; a molecule similar to ATP) produced in the citric acid
cycle via substrate level phosphorylation.
5. Twelve of the 16 hydrogens (6 NADH) released in the citric acid cycle, to yield 15 ATPs (6
NADH × 2.5 ATP per NADH = 15 ATP).
6. Four hydrogens joined to FAD (two FADH2 ) in the citric acid cycle to yield three ATPs.
Location
Partly in the cytosol and partly in the mitochondria.
How is energy produced from lipids?
Lipid mobilization and catabolism involves seven discrete processes:

1. Breakdown of triacylglycerol to free fatty acids. Hormone-sensitive lipase stimulates fatty

acids to diffuse from the adipocyte into the circulation.
2. Transport of free fatty acids in the blood. Fatty acids usually bind to plasma albumin for
transport to active tissues as free fatty acids (FFA).
3. Uptake of free fatty acids from blood to muscle. At the muscle site, the albumin–FFA complex
releases FFAs for transport by diffusion and/or a protein-mediated carrier system across the
plasma membrane. Once inside the muscle fiber, FFAs accomplish two tasks:
a. Re-esterify to form triacylglycerols
b. Bind with intramuscular proteins and enter the mitochondria for energy metabolism
by action of carnitine acyltransferase located on the inner mitochondrial membrane.
Carnitine acyltransferase catalyzes the transfer of an acyl group to carnitine to form
acylcarnitine, which can easily cross the mitochondrial membrane. Medium- and
short chain fatty acids do not need this mechanism. They can move freely into the
mitochondria on their own.
4. Preparation of fatty acids for catabolism (energy activation)
5. Entry of activated fatty acid into muscle mitochondria
6. Breakdown of fatty acid to acetyl-CoA via β-oxidation and the production of NADH and FADH2
7. Coupled oxidation in citric acid cycle and electron transport chain
Beta oxidation
Fatty acid molecules transform into acetyl-CoA in the mitochondria during beta (b)-oxidation. ATP
phosphorylates this reaction, water is added and H+ is passed to NAD+ and FAD. The long fatty acid
chain is successively split at 2-carbon acyl fragments. Acyl fragments join with coenzyme A to form
acetyl-CoA. This is the same acetyl-CoA that is formed from glycolysis. These then enter the citric acid
cycle.

Note that fatty acid breakdown relates directly to oxygen consumption. Oxygen must join with
hydrogen for β-oxidation to proceed. Under anaerobic conditions, hydrogen remains with NAD+ and
FAD, thus halting fat catabolism.
Citric acid cycle

Oxidative phosphorylation

How much ATP

The breakdown of a fatty acid molecule progresses in three stages as follows:

1. β-oxidation produces NADH and FADH2 by cleaving the fatty acid molecule into 2-carbon acyl
fragments.
2. Citric acid cycle degrades acetyl-CoA into carbon dioxide and hydrogen atoms.
3. Hydrogen atoms oxidize via electron transport–oxidative phosphorylation.

For each 18-carbon fatty acid molecule, 147 molecules of ADP phosphorylate to ATP during β-
oxidation and citric acid cycle metabolism. Each triacylglycerol molecule contains three fatty acid
molecules to form 441 ATP molecules from the fatty acid components (3 × 147 ATP). Also, 19 ATP
molecules form during glycerol breakdown to generate 460 molecules of ATP for each triacylglycerol
molecule catabolized
Glycerol
The anaerobic reactions of glycolysis accept glycerol as 3-phosphoglyceraldehyde. This molecule then
degrades to pyruvate to form ATP by substrate-level phosphorylation.

Location

What energy systems are used at different exercises intensities (duration) and why?
As muscle activity increases from low to high intensity, the liver increases glucose release to the
active muscle. Simultaneously, muscle glycogen supplies the predominant carbohydrate energy
source during the early stages of exercise and as intensity increases.

- Carbohydrate remains the preferential fuel in intense aerobic activity because it rapidly
supplies energy as ATP (see Chapter 6) via oxidative processes.
- During anaerobic exercise that requires glycolysis carbohydrates become the sole fuel for ATP
resynthesis.

increasing carbohydrate oxidation by ingesting high-glycemic carbohydrates prior to exercise (with

accompanying hyperglycemia and hyperinsulinemia) inhibits two processes:

- Long-chain fatty acid oxidation by skeletal muscle.

- Free fatty acid (FFA) liberation from adipose tissue.

Carbohydrate availability also reduces fat use for energy. With adequate glycogen reserves,
carbohydrate becomes the preferred fuel during intense aerobic exercise because of its more rapid
rate of catabolism. Toward the end of prolonged exercise (when glycogen reserves become nearly
depleted), fat, mainly as circulating FFAs, supplies up to 80% of the total energy requirement.
Intracellular and extracellular fat (FFAs, intramuscular triacylglycerols, and circulating plasma
triacylglycerols bound to lipoproteins as VLDLs and chylomicrons) supply between 30 and 80% of the
energy for physical activity, depending on nutritional and fitness status and exercise intensity and
duration  fat used for energy in light and moderate exercise is three times that compared to resting
conditions  As activity becomes more intense (greater percentage of aerobic capacity), adipose
tissue release of FFAs fails to increase much above resting levels, leading to a decrease in plasma FFAs
 This in turn stimulates increased muscle glycogen use.

The major energy for light-to-moderate exercise comes from fatty acids released from triacylglycerol
storage sites and delivered to muscle as FFAs and intramuscular triacylglycerols.

Regular aerobic exercise profoundly improves long-chain fatty acid oxidation, particularly from
triacylglycerols within active muscle during mild-to-moderate–intensity exercise.

The nutrient mixture for energy depends on the relative exercise intensity (i.e., the percentage of
one’s maximum exercise capacity)

High intensity exercise: Neural–humoral factors during intense exercise increase the output of
epinephrine, norepinephrine, and glucagon and decrease insulin release  These hormonal
responses activate glycogen phosphorylase  facilitates glycogenolysis in the liver and active muscles
 liberates glucose from glycogen for the active muscle.

- One hour of intense physical activity decreases liver glycogen by about 55%
- a 2-hr strenuous workout almost depletes the glycogen of the liver and active muscles.

Moderate and prolonged exercise: Glycogen stored in active muscles supplies almost all of the
energy in the initial transition from rest to moderate exercise  during the next 20 minutes: 40 and
50% of the energy requirement comes from liver and muscle glycogen, the rest from fat catabolism
and a limited amount of protein  As exercise continues and muscle glycogen decreases. Blood
glucose (from liver) becomes the major source of carbohydrate energy, while fat catabolism furnishes
an increasingly greater percentage of the total energy.  Eventually, the liver’s glucose output fails to
keep pace with glucose use by muscle, and plasma glucose concentration decreases. Blood glucose
levels may reach hypoglycaemic levels  circulating fat, predominantly as free fatty acids (FFA),
increases dramatically. Also the contribution of protein to the energy expenditure increases 
Exercise intensity, expressed as percentage of maximum, also progressively decreases under the
glycogen depleted condition. Reduced power output is a direct result of the relatively slow rate of
aerobic energy release from fat oxidation.

Low intensity exercise: fat serves as the main energy substrate throughout exercise.

At rest: Fat provides as much as 80 to 90% of the energy requirement of a well-nourished individual
at rest.