Exercise Tolerance and Fatty Acid Breakdown

When exercising, the body needs more ATP to fuel ATPases which are involved in the contraction-relaxation-cycle of muscles, mainly the calcium ATPase and the myosin ATPase. During aerobe exercise the body increases glycogen breakdown to glucose and metabolizes more triacylglycerides via fatty acid oxidation. Fatty acid oxidation is important for maintaining aerobe respiration. If anaerobe respiration is activated, oxygen deficit lowers respiratory chain function and the pyruvate dehydrogenase is inhibited. Pyruvate reacts to lactate with NADH/H+. The energy is produced from glycolysis and creatine phosphate.

The fatty acid oxidation produces FAHD2 and NADH/H+ independent from the citric acid cycle. This activates the respiratory chain and increases ATP. FADH2 can pass on two electrons and protons to coenzyme Q10, forming QH2 and FAD.

The enzyme pyruvate carboxylase needs ATP and bicarbonate. It catalyzes the reaction from pyruvate to oxaloacetate. Oxaloacetate and acetyl-CoA can then form citrate which fuels the citric acid cycle. This enzyme is very important for acetyl-CoA from the fatty acid oxidation and the pyruvate dehydrogenase to enter the citric acid cycle. This means that the citric acid cycle supplies the respiratory chain with NADH/H+ and FADH2, producing ATP, and at the same time ATP is a cofactor that helps more acetyl-CoA go into the citric acid cycle with the pyruvate carboxylase. The pyruvate carboxylase is one of the most important enzymes for increasing the pool of citric acid cycle metabolites (1).

Fatty acid oxidation might play an important role in providing more ATP for the pyruvate carboxylase during exercise to keep aerobe respiration active.

 

Another pathway to support aerobe metabolism is the conversion of propionyl-CoA to succinyl-CoA. During fatty acid oxidation small units are broken down from the long fatty acid and form acetyl-CoA. When odd-numbered fatty acids are oxidized, the last unit is a propionyl-CoA instead of an acetyl-CoA, which needs to be metabolized differently. It can be converted to succinyl-CoA with cofactors like bicarbonate and adenosylB12. The amino acids valine, isoleucine, threonine and methionine can also produce propionyl-CoA.

Succinyl-CoA enters the citric acid cycle or can be used for heme synthesis. The first reaction in the citric acid cycle is:
Succinyl-CoA + GDP + phosphate -> Succinate + GTP + Coenzyme A

GTP activates G-proteins and plays an important role in calcium signaling, because a G-protein subtype stimulates the enzyme phospholipase C, which excretes calcium into the cell via inositol triphosphate receptor. Calcium is a cofactor in the mitochondrial enzymes pyruvate dehydrogenase, the isocitrate and ketoglutarate dehydrogenases in the citric acid cycle and the glycerol 3-phosphate dehydrogenase (more in: Theories-> Calcium Signaling and G-proteins).

Calcium loading, elevated calcium concentrations over an extended amount of time also inhibit the energy metabolism (2). Both ATP and GTP help prevent this by removing calcium from the cytosol into the calcium storage and out of the cell with ATPases. GTP can fuel ATP levels with the enzyme nucleoside diphosphate kinase (3), and therefor contribute to releasing calcium and also lowering it again.

The glycerol 3-phosphate shuttle transfers NADH/H+ from the cytosol into the mitochondria, as it cannot pass the mitochondrial membrane. The shuttle does this by binding the electrons and protons from NADH/H+ in glycerol 3-phosphate and then to forming FADH2 at the respiratory chain (picture here). The glycerol 3-phosphate shuttle raises NAD+ in the cytosol, which increases glycolysis and reduces lactate and glycerol 3-phosphate stimulates the respiratory chain (more in: Post->Glycerol 3-phosphate shuttle).
Therefor GTP can increase the mitochondrial energy metabolism and help maintain aerobe respiration and activate pyruvate dehydrogenase during exercise. Reduced calcium uptake and release from the calcium storage into the cell, as well as decreased branch-chained amino acids (isoleucine, valine, leucine) are involved in fatigue after exercise (4).

After GTP-synthesis, the next reaction in the citric acid cycle is: succinate + FAD-> fumarate + FADH2
This reaction is coupled to complex II of the respiratory chain.

The pyruvate dehydrogenase is inhibited by high levels of acetyl-CoA, NADH/H+ and ATP. Both parts of fatty acid breakdown, the fatty acid oxidation and the odd-numbered fatty acid breakdown raise NADH/H+ and acetyl-CoA relatively little, while increasing GTP and ATP. The fatty acid oxidation forms one FADH2 for every NADH/H+ and acetyl-CoA produced and the odd-numbered fatty acid breakdown doesn’t form any acetyl-CoA and only one NADH/H+ on one GTP and FADH2 until it is converted to oxaloacetate. Pyruvate being broken down in the citric acid cycle, produces one acetyl-CoA and four NADH/H+ on one FADH2 and one GTP.

 

Low ATP, low GTP and impaired calcium release might cause a jam that prevents pyruvate from being metabolized in the citric acid cycle, because of lack of calcium as cofactor and low pyruvate carboxylase activity. This inhibits the aerobe metabolism during exercise and leads to more activation of the anaerobe metabolism with increases of lactate and cytosolic NADH/H+.

 

 

Bicarbonate

Bicarbonate (HCO3-) is a cofactor for both the pyruvate carboxylase and the odd-numbered fatty acid breakdown, which might be a reason why it is important for exercise tolerance. It is also needed in the fatty acid synthesis, which synthesizes the pyruvate dehydrogenase cofactor alpha lipoic acid.

Carbon dioxide and water react to bicarbonate:
CO2 + H2O <-> H2CO3 <-> HCO3- + H+
carbon dioxide + water <-> carbonic acid <-> bicarbonate + protons

Bicarbonate acts as a buffer. It can raise the pH, make it more alkaline by binding protons in carbonic acid. This reaction from bicarbonate to carbonic acid is increased, when proton levels rise too much, the pH becomes too acidic.

These two factors might help raise bicarbonate: enough CO2 and not too high proton levels. CO2 is a product of the citric acid cycle and synthesis increases with citric cycle function. The citric acid cycle and other processes that raise NADH/H+ also raise protons.

The respiratory chain uses the protons and electrons from NADH/H+ for ATP synthesis and complex IV of the respiratory chain binds protons in water: O2 + 4H+ +4e- -> 2H2O
Respiratory chain complex IV needs heme and copper as cofactors.

Pyruvate carboxylase raises CO2 levels in the citric acid cycle and the odd-numbered fatty acid breakdown might increase heme synthesis from succinyl-CoA.

 

In conclusion, fatty acid breakdown is important for raising ATP and GTP levels, which help increase aerobe respiration during exercise by activating pyruvate carboxylase and calcium release into the cell. Bicarbonate is a relevant cofactor and mediator of these processes.

 

References:

  1. https://www.ncbi.nlm.nih.gov/pubmed/6748086
  2.  https://link.springer.com/article/10.1007/BF00973148
  3. https://en.wikipedia.org/wiki/Nucleoside-diphosphate_kinase
  4. https://books.google.se/books?id=q8aVVxGjYnEC&lpg=PP1&hl=de&pg=PA165#v=onepage&q&f=false

Image of the respiratory chain