Case 2: running on empty

Carbohydrate loading: what is it, how does it work? Could you run the 30 km
Van Loon, Jeukendrop

CHO ingestion during prolonged exercise at moderate intensities can increase time to exhaustion and,
therefore, CHO ingestion has become widespread among athletes, both professional and amateur, in
a wide variety of sports. CHO ingestion leads to a better maintenance of blood glucose concentration
and increases the ability to maintain high CHO oxidation rates during more prolonged exercise
periods.

What is the effect of exercise intensity (MET) on substrate utilization

(absolute/relative intensity)
Couture S.

Higher workload during exercise increases the amount of exogenous carbohydrates burned. At high
absolute and relative workloads and for large amounts of carbohydrates ingested, the oxidation
rate of exogenous glucose plateaus around 1.0 - 2.4 glucose g/min, providing 25% of the energy yield.
Cycling seems to burn more carbohydrates then running in some studies.
At lower workload, running exercise (40% VO2max) or the amount of glucose ingested was small
around (0.4–0.8 g/min) of exogenous carbohydrates was burned.

Long distance runners often experience gastrointestinal discomfort when fed carbohydrates, possibly
due to impairment in gastric emptying and/or intestinal absorption. This could reduce availability
and oxidation of exogenous carbohydrates. However, Rehrer et al. (30) did not report any major
difference in gastric emptying in running and cycling at 70% VO2 max (3.15 l O2/min) with ingestion
of carbohydrates.

Couture et al found that during running exercise at a workload of (~3.0 l O2/min; 65–70% VO2 max)
for 2 hours, the oxidation rate of exogenous glucose over the last 40 min of exercise (1.12 g/min).
Different research at the same intensity levels found similar results (1.07 g/min).

A higher workload (80% VO2max) for shorter durations (60 to 90 minutes) only a small portion of
ingested glucose entered the plasma (22 vs. 84 g ingested), possibly due to a slow rate of gastric
emptying and intestinal absorption at such a high exercise intensity. During both cycling and running
exercise exogenous carbohydrate oxidation was also lower (0.54 and 0.40 g/min, respectively).

Most literature seems to agree that at a workload of 60% - 70% VO2max more exogenous
carbohydrate is oxidised then at 80% VO2mox. Longer exercise periods also seem to increase
exogenous carbohydrate oxidisation.
More exogenous glucose ingestion prior to exercise also tends to increase exogenous carbohydrate
oxidisation during exercise.

Exercising at higher intensity (>80% VO2max) causes the body to rely more on stored muscle glycogen
then plasma glucose oxidation. McConell et all showed that 80–83% VO2 max muscle glycogen
provides (3.1–3.4 g/min providing 70–82% of the energy yield) and plasma glucose oxidation (0.8–0.9
g/min).
In contrast, for the percentage of VO2 max ranging between 50 and 70%, the oxidation rate of plasma
glucose during cycling exercise is much higher, particularly if exogenous glucose is administered, and
the oxidation rate of muscle glycogen ranges only between 0.6 and 2.1 g/min, providing 20–58% of
the energy yield.

In summary, results from the present experiment suggest that during prolonged running exercise at
~70% VO2 max with ingestion of large amounts of glucose (~2 g/min), as already shown during
cycling exercise, exogenous glucose and plasma glucose, and not muscle glycogen, are the main
sources of glucose for oxidation, particularly at the end of exercise. During cycling exercise, the large
contribution of exogenous glucose oxidation to the energy yield reduces liver glucose output but does
not consistently reduce muscle glycogen utilization. When carbohydrates are ingested during running
exercise, no data are available concerning possible changes in liver glucose output, but consistent
data indicate that muscle glycogen utilization is reduced. In the present experiment, the large
oxidation rate of exogenous glucose was associated with a marked 37% reduction of endogenous
glucose oxidation (68 g between minutes 40 and 120). However, it cannot be ascertained whether
this was because of a reduction in muscle and/or liver glycogen utilization.

Stisen

Stisen et all found that in women the relative exercise intensity that elicited the highest fat oxidation
rate was around 55% of VO2max with no significant difference between trained and untrained
women.

Loon, Greenhaff

Fat oxidation at high intensity could be impaired because of unavailability of carnitine. Carnitine is a
co-factor that is required for the transport of long-chain fatty acids across the inner mitochondrial
membrane and is therefore essential for the oxidation of fatty acids in the mitochondria.

Loon et all found that the contribution of plasma FFA and TG fat sources was about 50 % each at each
exercise intensity.

The Rd of glucose equals its oxidation rate during moderate- to high-intensity exercise (Jeukendrup et
al. 1999).

There were no differences in total fat and carbohydrate oxidation rates when comparing these single
trials with the incremental protocol. The relative decrease in fat oxidation at 75 % Wmax tended to be
even greater when the subjects started exercise at the high intensity workload immediately after
warming up. This indicates that emptying of the intramuscular TG stores did not seem to play a role in
the reduction of fat oxidation observed at 75 % Wmax.

The table below shows substrates contribution and different exercise intensities.
Fat oxidation remains relatively similar at lower intensities (40% and 55%). However, as exercise
intensity was further increased up to 75 % Wmax, total body fat oxidation rate decreased by 34 ± 7 %
compared to that at the 55 % Wmax workload.

The reduction in body fat oxidation is not explained by a decrease in plasma FFA availability as that is
not decreased. The transport of FFAs across the plasma membrane may limit FFA uptake and
oxidation by muscle.

- Fatty acid translocase does not seem to be the problem. As exercise (muscle contraction) has
recently been shown to lead to parallel increases it’s activity.
- Kiens et al. (1999) observed an increase in intramyocellular FFA concentration in humans
when exercise intensity was increased from 65 to 90 % VO2,max, implying that the reduction
in fat oxidative capacity during high-intensity exercise is not determined by a reduced
intramyocellular availability of fatty acid.

Sidossis et al. (1997) showed in the setting of a constant plasma FFA availability that long-chain fatty
acid oxidation, but not medium-chain fatty acid oxidation, is inhibited during high-intensity exercise
and not during moderate-intensity exercise.

During high-intensity exercise (75 % Wmax), flux through the glycolytic pathway and the Pyruvate
Dehydrogenase Complex (PDC) reaction would greatly exceed flux through the TCA cycle, thereby
markedly increasing muscle lactate and acetylcarnitine concentrations and reducing free carnitine
availability.  a carnitine deficiency during high intensity exercise may be the cause of lower fat
oxidation as it is responsible for carrying long chain fatty acids into the mitochondria.

It may also be possible that during high-intensity exercise the free carnitine concentration declines to
a value that could limit Carnitine Palmitoyltransferase 1 (CPT 1) activity and reduce long-chain fatty
acid oxidation.
The observed decline in muscle free carnitine and parallel rise in acetylcarnitine concentration seems
to be intrinsically related to a decrease in CoA concentration in muscle. Most CoA is present in the
mitochondrial matrix, which may be a limiting factor for β-oxidation during high intensity exercise as
there is not enough CoA available.
At a very high workload it can be calculated that the entire pool of cellular CoA would have become
acetylated within 1s of the initiation of contraction. If this were to occur, the immediate result would
be the total inhibition of β-oxidation.

A decrease of the pH from 7.0 to 6.8 substantially reduced CPT I activity measured in vitro. However,
the relevance of this to the in vivo situation remains to be established.

What is the effect of exercise type/mode on substrate utilization? (running vs

weightlifting)
Koopman

A single resistance exercise session reduces both type I and II muscle fibre glycogen content, with
most pronounced changes located in the type IIx fibres. Furthermore, resistance exercise also reduces
intramyocellular lipid content in type 1 fibres.

Exercise-induced reduction in skeletal muscle glycogen and/or lipid content has been associated with
an increase in insulin sensitivity in humans. Skeletal muscle glucose uptake and glycogen synthase
activity strongly depend on muscle glycogen availability. This is related to increased GLUT4
translocation under reduced muscle glycogen availability, and is likely coupled to an increased
activation of AMP-activated protein kinase (AMPK).

A single resistance exercise session improves whole-body insulin sensitivity by ~13% for up to 24 h
after exercise. Which is of a similar magnitude as the ~20% increase in whole-body insulin sensitivity
has been reported after ~60 min of endurance exercise.

Koopman found that mixed muscle glycogen content declined by 33±7% following a resistance
exercise session. Net changes in muscle fibre glycogen content were more pronounced in type IIx
fibres compared to type I muscle fibres, which can be attributed to the greater recruitment of these
fibres during high-intensity resistance exercise. Furthermore, they observed a significant 27±7%
reduction in type I muscle fibre lipid content. No changes in IMTG content were observed in the type
IIa and IIx fibres.
On average, type I muscle fibre lipid content was 2.5±0.3 and 8.8±1.4 times greater when compared
to the type IIa and IIx fibres, respectively.

Interestingly, within 120 min of post-exercise recovery, muscle fibre lipid content had returned to pre-
exercise values. This could be attributed to the substantial increase in circulating plasma FFA
concentrations during post-exercise recovery.

This may be due to the greater oxidative capacity of type 1 fibres compared to type 2 fibres as fat
oxidation costs oxygen. Glycolysis can produce ATP anaerobically.

Stisen

Endurance training causes cellular adaptations include an increase in muscle glycogen content and in
the enzymes β-hydroxy acyl CoA dehydrogenase (HAD), Hormone-sensitive Lipase (HSL), and Citrate
Synthase CS, which contribute to a more efficient metabolism and concomitant improved metabolic
function.
By using a graded exercise test with many steps, Achten et al. (2002; 2003) and Achten and
Jeukendrup (2003) found that the fat oxidation rate peaked at exercise intensities between 62% ± 3%
and 64% ± 4% VO2max after which it rapidly decreased and became negligible at high-exercise
intensities.

What is the effect of training status on substrate utilization?

Stisen

Trained individuals have a greater potential for increased fat oxidation during exercise than untrained.
Trained subjects have a higher fat oxidation rate during submaximal exercise at same absolute
intensity. However, when measured at the same relative exercise intensity there is still some debate
whether the trained subjects have a higher fat oxidation rate than untrained subjects.

Stisen et all found that some studies have found a greater fat metabolism in women than in men at
the same relative exercise intensity. This corresponded with a highly significant correlation between
skeletal muscle HAD activity and fat oxidation rates at moderate and high intensities.

Some studies have found a greater fat metabolism in women than in men at the same relative
exercise intensity.

Stisen et all found over a wide range of exercise intensities in the moderate or high categories,
trained women rely more on fat oxidation than untrained women.

Stisen et all found that HSL(TG) activity was significantly increased in the trained compared with the
untrained women at medium and high intensities (120W – 160W). No difference was found at low
intensity (below 120W). some ascribed this increased reliance for fat oxidation to improved ability for
oxidation of non-plasma sources, particularly fat stored inside the muscle (Martin et al. 1993; Klein et
al. 1994; Phillips et al. 1996; Friedlander et al. 1998a, b; Carter et al. 2001).

The endurance trained women had significantly increased activity in the oxidative enzymes CS and
HAD. As CS activity reflects a more general oxidative capacity in the tricarboxylic acid cycle, HAD is a
predictor of a fat metabolising capacity since it represents the formation process of acetyl-CoA during
β-oxidation. HAD is a key enzyme in β-oxidation and the enzyme capacity is also elevated following a
fat-rich diet. Stisen found that the activity of HAD correlated significantly with both the fat oxidation
in the moderate and high category (relative intensities) as well as the fat oxidation observed at 150
W.

Intra muscular triglycerides (IMTG) contribute to energy production during prolonged exercise (van
Loon 2004). HSL is the enzyme which is thought to be at least partly responsible for the hydrolysis of
IMTG, and increased HSL activity indicates a potential for a more rapid lipolysis of TG stored in the
muscle. Even though the adrenaline-induced stimulation of HSL in the trained state is attenuated, a
corresponding elevation of the contraction-induced stimulation of HSL is thought to account for
increased activity and a further elevation in IMTG hydrolysis

Van Loon, Jeukendrop

Van Loon et all tested subjects exercising at the same absolute (148 W) and relative workload (50%
Wmax) while ingesting glucose.

- We observed that endurance-trained subjects have a substantially increased fat oxidation

during prolonged moderate-intensity exercise (37–50% Wmax) with glucose ingestion and
with the absence of glucose ingestion.
 - At the same relative workload (50% Wmax), we found a similar rate of Total Carbohydrate
Oxidation (TCO).  The higher energy expenditure (as absolute workload is higher) recorded
in the trained subjects was completely accounted for by the increased fat oxidation.
- When van Loon et all compared both groups during exercise at the same absolute workload,
fat contributed significantly more to total energy expenditure and, concomitantly, TCO was
decreased in the trained group.
o Training status had a significant effect on total muscle glycogen utilization during
prolonged exercise of moderate intensity with glucose ingestion only when
comparisons were made at the same absolute workload.
o When compared at the same relative workload, oxidation of glucose produced by the
liver (coming from gluconeogenesis and glycogenolysis) was not influenced by
training status.
o Oxidation rates of liver-derived glucose were significantly lower in the trained
compared with the untrained subjects when both were exercising at the same
absolute workload.

Some potential causes are:

- Hormonal changes in trained athletes that drive liver glucose output.

o Both decreases in plasma insulin and increases in epinephrine, norepinephrine, and
glucagon have been implicated in the control of glucose output during exercise.

Trained athletes have more mitochondria and better capitalisation which increases their oxidative
capacity.

Two statements in the case: is it true or is it not?

Trained athletes actually use less energy to complete the same effort as untrained athletes?

Trained runners will get more energy out of fat than untrained individuals?
Exogenous CHO oxidation
VO2max test

RER

Eqauations of Frayn

Concentration vs flux
Isotopes
14C falls apart and will able to fall apart into 13C.

Isotope tracker