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do not take into account that under aerobic physiological conditions oxygen is not a
limiting factor for energy metabolism, but instead that there are many other factors
to be taken into account in the whole system. And these factors were indeed taken
into account by nature. Regarding the fuel supply to such a high-energy demanding
organ as is the heart, Clark and collaborators were the first to show that glucose
constituted less than 1/4 of the substrates oxidized by the isolated working
frog heart (Clark et al. 1937 ). These authors were not able to figure out which
substrate(s) were responsible for consuming the remnant oxygen. In 1954, Bing and
collaborators showed that the respiratory quotient (RQ, VCO 2 /VO 2 ) in post-
absorptive state was about 0.7-0.75 while studying oxygen utilization during the
aerobic metabolism of fats, ketones, and amino acids by human heart (Bing
et al. 1954 ). This ratio was unchanged following overnight fasting but increased
above 1 after ingestion of a high fat diet. The authors assumed that this increase
could be due to utilization of intramuscular triacylglycerol (TAG) stores (Bing
et al. 1954 ). Similar data were obtained in skeletal muscle. The average respiratory
quotient (VCO 2 /VO 2 ) of muscular tissue taken from de-pancreatized dogs was
about 0.7 (Bing et al. 1954 ).
In the case of working heart, the preferential energy supply by FA can be
understood from calculations specifying energy needs to realize work, energy
content of different substrates per unit mass, and kinetics of reactions in Randle
and Krebs cycles, rather than by oxygen consumed for oxidizing different fuels. A
heart contracting with a frequency of 70 bpm exhibits a stroke volume of 0.07 L
(i.e., cardiac output—5 L/min) that supports a pressure of 13 kPa (equivalent of
120/70 mm Hg) and realizes a work equal to 65 J/min or 93.6 kJ/day. ATP
hydrolysis in the actomyosin reaction releases about 60 kJ/mol under physiological
conditions. For the heart to accomplish a work equivalent to 100 kJ/day about
2.8 mol of ATP are needed ( n
G ATP corrected for the reaction efficiency that
in the case of actomyosin is about 60 %). This amount of ATP can be obtained from
the oxidation of 0.074 mol glucose or 0.02 mol of palmitic acid. For glucose,
supplemented with an equivalent molecular weight of 10 mol of water, 26.5 g
glucose should be oxidized by the heart to perform work equivalent to 100 kJ/day.
For palmitic acid only 5.5 g of this FA are necessary to perform a similar amount of
work. Thus, the content of free energy per gram of mass that can be released during
oxidation and converted into chemical energy in the form of ATP is much higher for
FAs than for carbohydrates due to the much higher content of non-oxidized -C-C-
and -C-H chemical bonds. Depending on the amount of bound water the difference
in carbohydrates can range from three- to ninefold (Newsholme and Start 1973 )
(Fig. 11.5b ). Thus, the kinetics of mass transfer in substrate supply is much more
favorable when FAs, as compared to glucose, are used as substrates. And this fact
explains the choice made by nature: heart and oxidative skeletal muscle clearly
prefer FAs as substrates (Fig. 11.5a ). Their preferred utilization by heart and
oxidative muscle is achieved by multiple regulatory mechanisms involved in the
Randle and Krebs cycles (Fig. 11.4 ).
Randle et al. ( 1963 ) were the first to propose the concept of selective supply of
FAs over glucose for heart muscle (Randle et al. 1963 ). The glucose-FA cycle or
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