PHYSIOLOGY OF CARDIAC MUSCLE 



207 



associated with glyccraldehycle-deliydrogenase and 

 lactic dehydrogenase, must therefore react with 

 sarcosomal DPN+ to initiate hydrogen transport. The 

 report tliat ^-glycerophosphate is an obhgatory in- 

 termediate in the transfer of hydrogen from soluble 

 DPNH to mitochondrial DPN+ in insect flight muscle 

 has not been explored in licart muscle. \on KorfT & 

 Twedt (247) ha\e shown that heart mitochondria 

 will oxidize lactate in tlie presence ot added pinnfied 

 lactic dehydrogenase and DPN+, and Brin et al. (33) 

 ha\e shown that l( + ) lactate-U-C" is oxidized to 

 pyruvate-U-C'' and Cl^O, in heart slices. These 

 workers also showed that lactic dehydrogenase was 

 limiting in the oxidation of lactate in heart muscle. 

 The glycolytic reactions are essentially reversible 

 as indicated in equation i . DPNH and ATP are, of 

 course, required to regenerate hexose phosphate from 

 pyruvate, and both are a\ailable in the cardiac muscle 

 cell. Hexosediphosphate phosphatase is also present 

 in heart muscle and provides reversibility to the 

 phosphofructokinase step (fig. loV The phosphorvla- 

 tion of pyruvate liv ATP is accomplished with great 

 difficulty because the equilibrium of the pvruvic 

 kinase reaction shown below lies far to the right : 



carbohydrate 



phosphoenolpyrovate -{- ADP , ' pyruvate -|- .ATP 



(--) 



To circumxent this thermodynamic difliculty a 

 system exists in cardiac muscle and certain other 

 tissues for converting pyru\'ate to PEP (phospho- 

 enolpyruvate) without employing the pyru\'ic kinase 

 reaction. This sequence of reactions, known as the 

 Utter-Ochoa cycle, is shown in figure 10, and pro- 

 vides the means for converting pyruvate to PEP by 

 way oi malate and oxaloacetate. 



The first step, the conversion of pyruvate to malate, 

 catalyzed by "malic enzyme," was first demonstrated 

 in pigeon lix'er by Ochoa et al. (171). This TPNH 

 dependent reaction occurs in the sarcoplasm. Since 

 malate is freely diffusible, con\ersion of malate to 

 oxaloacetic acid can occur in the mitochondria, by 

 one of the established steps of the Krebs cycle. Utter & 

 Wood (243) discovered an enzyme which catalyzes 

 reversible reaction : 



CO; -|- phosphoenolpyruvatc -|- GDP 



^ o.xaloacetate -|- GTP (3) 



This reaction pro\ides a means for forming phospho- 

 pyruvate from oxaloacetic acid with much more 

 favorable equilibrium constant. The phosphoenol- 

 pyruvate-carboxvkinase reaction occurs in the mito- 



GTP 



TPNH 



TPN* 



oxolacetate 



DPN'^ 



FIG. 10. Utter-Ochoa pathway lor synthesis and break- 

 down of phosphoenolpyruvate. 



chondria and hence can make full use of oxaloacetic 

 acid present there. The oxaloacetic acid can then be 

 converted to PEP with the evolution of CO2. PEP 

 is convertible to glycogen by reversal of the reactions 

 of glycolysis. 



Cardiac muscle contains all the enzymes con- 

 cerned, although PEP carboxykinase is low in com- 

 parison with liver and kidney Ijut high in comparison 

 with skeletal muscle. Tlie "malic enzyme"' is present 

 in abundant amoimts in heart muscle, as is pyruvate 

 kinase. Stadie et al. (223) have shown rat heart slices 

 form glycogen from glucose, but were unable to dem- 

 onstrate glycogen formation from lactate, pyruvate, 

 or alanine. On the other hand, Lorber et al. (139, 140) 

 showed that C'^Os could be incorporated into the 

 glycogen of the isolated cat heart incubated with 

 glucose and lactate. These workers found that heart 

 glycogen acquired a substantial labeling under these 

 circumstances in a relatively short time and the 

 results suggest that the isolated heart has a capacity 

 of synthesizing glycogen by the dicarboxylic acid 

 pathway, by reversal of the pyruvic kinase reaction 

 or by both mechanisms. Glycogen synthesized from 

 pyruvate a-C" (239, 259) produced label in the i, 

 2, 5, and 6 positions of glycogen with almost equal 

 specific activity, suggesting that equilibration through 

 a dicarboxylic acid had occurred prior to resynthesis. 



In summary, glycolysis of glucose to pyruvate via 

 the Embden-Meyerhof pathway is an important 

 pathway in cardiac muscle, but is not sufficient to 

 generate enough ATP for the energy needs of the 

 heart nor to deliver 3-carbon compounds at the rate 

 required in the terminal oxidation pathway. The 



