Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

III. Heterogeneity of Skeletal Muscle
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E. Quantitative Biochemistry
1 . Metabolic Pathway for Utilization of Energy (ATP) for
Contraction
As previously discussed, the actin-activated myosin ATPase
activity catalyzes the cyclical physiochemical interactions
of actin and myosin during contraction ( Fig. 15-4 ).
Furthermore, the intrinsic speed of contraction (sarcomere
shortening) has been demonstrated to be proportional to
the activity of actin-activated myosin-ATPase, and differences
exist between the myosin-ATPase activities of type I
and type II muscle fibers. From those observations it is postulated
that the rate-limiting step of sarcomere shortening
during contraction is the hydrolysis of ATP. The ATPase
activity of type I fibers is lower than in type II fibers, and
their pH dependency and liability in acid and alkaline conditions
also differ ( Barany, 1967 ; Seidel, 1967 ).
2 . Metabolic Pathways That Generate Energy (ATP) for
Contraction
Quantitative differences in enzyme activities and various
substrate concentrations have been reported between slowtwitch
type 1 and fast-twitch muscle fibers type 2 as well
as between fibers expressing myosin isoforms type 2a and
2x. Those biochemical differences between fiber types
reflect differences in their principal metabolic pathways
active in the generation of energy (ATP) for muscular contraction
( Fig. 15-7 ).
The ATP required for contraction is not stored in significant
quantities. Therefore, ATP must be readily produced
through the metabolism of fats, carbohydrates, and creatine
phosphate stores to support the energy requirements for
contraction. Aerobically, ATP is produced in muscle mitochondria
by oxidative phosphorylation coupled to electron
transport. Anaerobically, ATP is produced in the aqueous
sarcoplasm through substrate phosphorylation of ADP by (1)
creatine kinase, utilizing creatine phosphate stores; (2) glyco-
(geno)lysis, utilizing muscle glycogen stores, and (3) myokinase
kinase, utilizing ADP produced by the ATP hydrolysis.
a . Aerobic and Anaerobic Energy Metabolism
In general, fast-twitch muscle fibers in the untrained state
are biochemically suited to derive energy for contraction
by anaerobic glyco(geno)lysis. Fast-twitch fibers, particularly
type IIx, tend to have higher concentrations of glycogen
and creatine phosphate as well as higher activities
of enzymes associated with glycogenolysis and glycolysis
( Table 15-1 ). Slow-twitch type I fibers, on the other hand,
generally have higher concentrations of triglycerides and
myoglobin and are better suited to derive their energy by
oxidative phosphorylation via the electron transport system
following the oxidation of fatty acids and glucose via the
Krebs cycle ( Table 15-1 ). Type IIa fibers are intermediate
in their glycolytic and oxidative capacity between type IIx
and type I fibers ( Adhihetty et al. , 2003 ; Rubenstein and
Kelly, 2004 ).
Triglycerides and glycogen serve as primary substrates
for muscle metabolism. In general, the rate of glycogen
utilization is greatest with high-intensity anaerobic exercise,
whereas low-intensity submaximal exercise results in
a lower rate of glycogen utilization and reliance on oxidation
of fatty acids as fuel ( Kiens, 2006 ). Under conditions
of restricted energy intake or prolonged exercise, amino
acids may also serve as energy substrates within skeletal
muscle ( Rennie et al. , 2006 ).
b . Purine Nucleotide Cycle
With strenuous exercise when the regeneration of ATP
fails to meet energy demands, the myokinase reaction
can be used to generate ATP from accumulated ADP.
The accumulation of the additional product of this reaction,
AMP, stimulates the purine nucleotide cycle, which
removes AMP thereby preventing product inhibition of the
myokinase reaction. The deamination of AMP by AMP
deaminase in the purine nucleotide cycle results in the production
of ammonia and inosine monophosphate (IMP)
( Lowenstein, 1972 ). The cycle further involves the regeneration
of AMP through deamination of aspartate and the
hydrolysis of guanosine triphosphate to form adenylosuccinate,
and the cleavage of adenylosuccinate to form fumarate
and AMP. The activity of AMP deaminase is greater in
type II compared to type I muscle fibers.
The purine nucleotide cycle regulates energy requirements
for muscular contraction through (1) maintenance
of a high ATP:ADP ratio by regulating the relative AMP,
ADP, and ATP levels; (2) regulation of phosphofructokinase
(PFK) activity through activation of this enzyme by
ammonia; (3) regulation of phosphorylase activity through
activation by IMP; (4) replenishment of citric acid cycle
intermediates by the production of fumarate; and (5) deamination
of amino acids for oxidative metabolism through
the formation of aspartate ( Tullson and Terjung, 1991 ).
From the foregoing, it is evident that the deamination
of AMP can promote ATP synthesis by (1) stimulating
anaerobic glyco(geno)lysis through the activation of phosphorylase
b by IMP, and the activation of PFK by ammonia,
and (2) supporting oxidative metabolism through the
production of intermediates into the TCA cycle. The degradation
of adenine nucleotides in equine muscle appears to
occur mainly through deamination of AMP. Reported AMP
deaminase activities are greatest for equine middle gluteal
muscles, which were approximately double reported values
for muscles of the rat and rabbit ( Cutmore et al. , 1986 ).
c . AMP Kinase
Another emerging key sensor and regulator of energy
metabolism in skeletal muscle is AMP-activated protein