section 21.3
Energy Supply in Muscle
supply. For all of these reasons, protein metabolism is not a
preferred pathway for energy supply. Nevertheless, protein
metabolism contributes 2-3% of the energy requirement
in exercise of a few minutes duration and rises to as much
as 12% after several hours of physical work. Replenish-
ment of TCA cycle intermediates such as a-ketoglutarate
(derived from glutamate) or oxaloacetate (from aspartate
or asparagine) is probably important to offset the loss of
TCA cycle intermediates from mitochondria over time.
This role of protein catabolism in supporting glucose and
lipid oxidation, called
may be more impor-
tant than its direct contribution to energy supply.
Nitrogen transport from muscle to liver seems to be
accounted for mainly by release from muscle of alanine
d e novo
by amination of pyruvate. Liver pro-
duction of urea, however, is thought to be driven mainly
by plasma glutamine and ammonia concentrations. Mus-
cle release of glutamine does not increase during exercise
(although ammonia efflux increases), nor does the plasma
glutamine concentration, and there is no significant in-
crease in urea production during exercise of moderate in-
tensity and duration. Most alanine reaching the liver in this
circumstance is deaminated and used in gluconeogenesis,
but the immediate disposition of the amino nitrogen is still
Special significance is often attributed to branched-
chain amino acids (BCAAs: leucine, isoleucine, and va-
line) in the context of muscular performance. Increased
BCAA uptake and oxidation by muscle does occur dur-
ing exercise, and it has been claimed that intramuscular
BCAA concentration exerts a regulatory influence on rate
of protein synthesis. It is also claimed that, since BCAA
and tryptophan (TRP) compete for transport across the
blood-brain barrier, decreasing plasma BCAA concentra-
tion leads to increased brain TRP uptake and serotonin
synthesis and a host of putative effects thereof. Although
these hypotheses are attractive and a segment of the sup-
plement industry relies on them, available studies show
that BCAA supplementation in humans neither offers any
performance benefit over other energy supplements nor
alters mood or perception during or after exercise.
purine nucleotide cycle
also is involved in muscle
energy production. During intense stimulation, or when O
supply is limited, the high-energy bond of ADP is used to
synthesize ATP via the myokinase reaction (Figure 21-12).
The resulting AMP can dephosphorylate to adenosine,
which diffuses out of the cell. Conversion of AMP to
IMP via adenylate deaminase and then to adenylosucci-
nate helps sustain the myokinase reaction, especially in
FG fibers, by reducing accumulation of AMP. It may also
reduce the loss of adenosine from the cell, since nucleo-
sides permeate cell membranes while nucleotides do not.
2A D P
(m yokinase)
F u m a r a t e
. ,
A d en ylo su cc in a se/
deam inase'
/A denylosuccinati
. ,
Adenylosuccinate --------
^ 'S 'S
G D P + F> G T P Aspartate
(crosses the cell m em brane)
FIGURE 21-12
Role of purine nucleotides in muscle energy metabolism. The conversion
of AMP to IMP prevents loss of adenosine from the cell.
Lack of muscle adenylate deaminase has been found
in some muscle disorders in which other abnormalities
could not be identified. Failure to produce ammonia dur-
ing intense effort may be diagnostic. In the heart, AMP
accumulation is typically due to ischemia, and the adeno-
sine released as a result is a potent coronary vasodilator.
Accordingly, myocardium has less adenylate deaminase
than skeletal muscle. However, large losses of adenosine
from myocardium are dangerous because they lead to a
decrease in ATP concentration that does not respond to di-
lation, thrombolytic, or oxygen therapy. Lack of adenosine
deaminase in lymphoid tissue causes a severe immunode-
ficiency (Chapter 27).
Phosphocreatine Shuttle
Energy transfer between mitochondria and the myofibril-
lar ATPases is mediated by phosphocreatine (Chapter 17).
The phosphocreatine shuttle is illustrated schematically in
Figure 21-13. Synthesis of ATP in mitochondria is closely
coupled to that of phosphocreatine. Since the reaction
ATP + C -* ADP + P ~ C
is energetically favored when the ATP/ADP ratio is high,
phosphocreatine is rapidly formed from ATP releasing
ADP, which stimulates mitochondrial respiration. Phos-
phocreatine diffuses from the mitochondria to the various
sites of energy utilization, where CK reverses this reaction
to form ATP and creatine. Creatine diffuses back to the
mitochondria for rephosphorylation. Since creatine elicits
formation of ADP in mitochondria, the increase in creatine
helps stimulate respiration when muscle activity increases.
Cellular adenine nucleotides are compartmentalized by
their very low diffusibility (due to their size and charge)
with pools in the mitochondria, at the myofibrils, SR, and
other sites of energy utilization. CK is located at those
sites. Phosphocreatine is much smaller and less charged,
and therefore much more mobile in cells than ATP. ATP
produced by substrate-level phosphorylation in glycolysis
may be used to rephosphorylate creatine in the sarcoplasm;
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