2.1 Overview of glucose metabolism in the cytosol (glycolysis) under anaerobic conditions
Carbohydrate (intramuscular glycogen) is the only macronutrient that generates ATP anaerobically hence it is the next fastest energy source needed to fuel initial energy demands. ATP resynthesis from the anaerobic catabolism of glycogen is termed glycolysis.
Glycolysis has two phases.
- In the first phase, a series of five reactions, glucose is broken down to two molecules of glyceraldehyde-3-phosphate with the use of 2 ATP molecules.
- In the second phase, five subsequent reactions convert the two molecules of glyceraldehyde-3 phosphate into two molecules of pyruvate, generating 4 molecules of ATP. The net ATP production in glycolysis is two molecules of ATP through substrate-level phosphorylation (Figure 2).
Figure 2. Anaerobic breakdown of glucose in the cytosol (for more detail, please consult McArdle, Katch & Katch, Fig. 6.11)
Several features of these reactions and skeletal muscle cells make glycolysis a fast and highly controlled step in ATP resynthesis. For example, phosphofructokinase (PFK) is one of the important regulators of the rate of glycolysis (often called a “rate limiting enzyme”). The activity of PFK increases when energy is needed, as ATP levels are low and AMP levels are high, and PFK activity decreases otherwise. Fast-twitch muscle fibers contain relatively large quantities of PFK, making them ideally suited for generating anaerobic energy via glycolysis.
2.2 Byproducts of Glycolysis and Lactate Shuttle
The additional products of glycolysis are 2 extra-mitochondrial NADH (carrier molecule for hydrogen) and 2 pyruvate molecules. NAD+ constitutes a limiting step in glycolysis. NAD+ can be recycled via aerobic or anaerobic pathways, either of which results in further metabolism of pyruvate. Under aerobic conditions (O2 is plentiful), pyruvate is converted to acetyl-coenzyme A (acetyl-CoA), which is fully oxidized in the citric acid cycle (described in section 2.3).
When skeletal muscles are exercised strenuously, the available oxygen is consumed and the energy demand exceeds oxygen supply or the rate of oxygen utilization. Hence, the electron transport chain, which oxidizes NADH to NAD+ in the presence of O2 (described further in section 2.4), cannot process all the hydrogen joined to NADH due to unavailability of O2. As a result, continual ATP production depends on the reduction of excess pyruvate into lactate by the enzyme, lactate dehydrogenase and the anaerobic oxidation of NADH into NAD+ to enable the continuation of glycolysis and the rapid, anaerobic and limited ATP resynthesis (Figure 3). Lactate accumulation in the environment of the muscle results in decreased pH (acidic environment), which slows muscle contraction, enzymatic reactions and contributes to muscle fatigue. Lactate accumulation is often felt by the exerciser as “burning” or “heaviness” in the muscles.
When sufficient oxygen becomes available or the exercise pace slows, NAD+ collects back the two hydrogens attached to lactate to form pyruvate, which can be oxidized for energy or converted into glucose (gluconeogenesis) via the Cori cycle. The Cori cycle occurs in the liver and kidneys to sustain glucose levels. Also, fast-twitch muscle fibers are important in the distribution of lactate to other tissues (lactate shuttling) for its conversion to pyruvate. Neighboring slow-twitch muscle fibers which have a greater ability to extract and utilize oxygen than fast-twitch fibers, can take up lactate, convert it back to pyruvate for entry into the citric acid cycle and resume with aerobic ATP production after an anaerobic episode. Similarly, cardiac muscle is able to take up lactate and utilize it for aerobic metabolism (Figure 3).
Figure 3. Destiny of lactate in the presence and absence of oxygen.
2.3 ATP resynthesis from glucose in the mitochondrion under aerobic conditions
The mitochondrion is where aerobic ATP generation occurs through the citric acid cycle, beta-oxidation, and electron transport chain. In the glycolysis pathway, a molecule of glucose is converted in 10 enzyme-catalyzed steps to two molecules of 3-carbon pyruvate as shown in Figure 2.
The two pyruvates must enter the mitochondrion and prepare to enter the citric acid cycle by each joining with coenzyme-A to form two acetyl-CoA. Under the enzymatic control of pyruvate dehydrogenase and the reduction of NAD+ to NADH+, each pyruvate molecule is decarboxylated to form acetic acid, which once combined with 2 molecules of CoA, two acetyl-CoA are formed (equation 4):
Equation 4: Formation of Acetyl-CoA from pyruvate
The two acetyl-CoA enter the citric acid cycle to be fully oxidized into CO2 as depicted in Figure 4.
Figure 4. Schematic of the release of hydrogen and carbon dioxide in the mitochondrion during the breakdown of one pyruvate molecule (for more detail, please consult McArdle, Katch & Katch, Fig 6.15).
In the first reaction of the citric acid cycle, the acetyl portion of each acetyl-CoA joins with one oxaloacetate to form one citrate molecule. In two turns of the cycle, two acetyl-CoA are oxidized into 4 molecules of CO2, 6 molecules of H2O, 2 GTP (substrate level phosphorylation, equivalent to 2 ATP) and 6 NADH (carrier of 12 H+) and 2 FADH2 (carrier of 4 H+) to generate ATP through the electron transport chain or oxidative phosphorylation.
2.4 Electron Transport Chain
Hydrogen released during glycolysis and the citric acid cycle are “accepted” by two carrier molecules, NAD+ (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide) in a reduction reaction and become NADH+H+ and FADH2. Through a series of oxidation and reduction reactions (REDOX reactions) the free electrons are passed from a high energy state to low energy state through iron-rich compounds called cytochromes. The final acceptor in the chain is oxygen, which accepts hydrogen to form water. The energy that is released from the series of REDOX reactions as the electrons move from a high energy state to a low energy state, is synthesized into ATP through the process called oxidative phosphorylation. These reactions occur across the inner membrane of the mitochondrion. In this process, each NADH+H+ yields 3 ATP and each FADH2 yields 2 ATP, therefore the electron transport chain produces a large number of ATP. (FADH2 yields fewer ATP as it enters the chain at a lower energy state than NADH). It is important to note that oxygen is required in the electron transport chain as the final hydrogen acceptor.
Figure 5. The electron transport chain removes electrons from hydrogens for ultimate delivery to oxygen. In oxidation–reduction, much of the chemical energy stored within the hydrogen atom becomes conserved within ATP (for more detail, consult McArdle, Katch & Katch, Fig 6.7a)
2.5 Summary of ATP Production from complete breakdown of glucose
The complete breakdown of glucose yields a total of 38 ATP, but because 2 ATPs are used in the initial glycolysis reactions, the net ATP yield from glucose catabolism in skeletal muscle is equivalent to 36 ATP.
2.6 Comparison of the energetic yield in aerobic vs. anaerobic conditions
The anaerobic energy contribution provided by direct ATP hydrolysis, phosphocreatine, adenylate kinase reaction and glycolysis (breakdown of one molecule of glucose) are rapid sources of energy, but do not compare to the 36 ATP contributed by one glucose molecule under aerobic conditions. Rapid glycolysis generates only about 5% of the total ATP during the glucose molecule’s complete degradation to energy (2 ATP/36 ATP) therefore ATP generation from glycolysis can only support short-lasting periods of physical activity. Conversely, the citric acid cycle generates 6 NADH and 2 FADH2 producing 22 ATP through oxidative phosphorylation (electron transport chain) and 2 ATP through substrate level phosphorylation (GTP to ATP in the citric acid cycle).
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