5. Managing Energy Needs During Extreme Exercise

Whenever a healthy person experiences extreme exercise, such as running a 500 meter dash, the muscles are challenged to come up with sufficient ATP to satisfy their energy needs. Both oxygen and glucose can become depleted. To compensate for these deficiencies, muscle cells have devised a complex set of strategies, which operate in the cytoplasm instead of in the mitochondria. They involve a number of enzymes that will resurface later in our story, since they are the enzymes that are monitored to determine whether statin drugs are damaging muscles and/or the liver.

As you've already seen, one option is to generate lactic acid anaerobically (without consuming oxygen), but this still provides only 1/6 as much ATP as the aerobic process taking place in the mitochondria. The process of generating energy from ATP happens in two steps: ATP is first converted to ADP (adenosine diphosphate) and finally to AMP (adenosine monophosphate). When excess amounts of AMP accumulate in the muscle cell, the cell is induced to take up extra glucose, which will soon deplete the supply (of glucose) in the blood unless the liver can efficiently regenerate more. ADP can be converted back to ATP with the help of an enzyme, creatine kinase. In addition, the conversion of pyruvate (generated anaerobically from glucose) to lactate requires the help of another enzyme, lactate dehydrogenase. Lactate builds up when oxygen is insufficient, and is released into the blood stream. Fortunately, the heart is able to utilize lactate as an alternative fuel source [9], which becomes especially important during times of extreme exercise.

In order for the liver to generate more glucose, it needs a substrate. In the short term, muscles can supply this substrate, but it requires self cannibalization. During brief periods of starvation, human muscle cells adapt quickly by breaking down muscle proteins and converting them into a basic amino acid, alanine [34]. Muscles then rely on a novel mechanism that involves an exchange system with the liver, the so-called glucose-alanine cycle. The alanine, derived from muscle protein, is released into the blood and shipped to the liver to be utilized for energy generation, as shown in the accompanying figure. The liver can then generate more glucose from the alanine through gluconeogenesis, while exporting the waste product, urea, to the kidneys for excretion. This also allows the liver to regenerate some ATP to help satisfy its own energy needs, which are very large during such stressful conditions. The glucose is shipped through the blood stream to the muscle cell, which eagerly takes it up to generate more ATP for itself. The anaerobic processing of glucose yields pyruvate which can also be turned into alanine, but it needs yet another enzyme to work. Thus, whenever pyruvate can't be sent to the mitochondria because of insufficient oxygen, it can instead be converted to alanine with the help of an enzyme, ALT (alanine aminotransferase), as long as there is a good supply of glutamate, which is converted to alpha-keto glutarate in the process.

In the above discussion, several enzymes have been identified that must be present for these cytoplasmic energy-generating processes to function. These include creatine kinase, lactate dehydrogenase, and ALT. The so-called liver enzyme test that is conducted routinely with statin users measures the concentration of ALT in the blood. Muscle enzyme tests detect creatine kinase and lactate dehydrogenase concentrations in the blood. So these tests are all measuring these particular enzymes because they signal that muscles are preferentially processing glucose anaerobically in the cytoplasm instead of aerobically in the mitochondria; i.e., the mitochondria are not working properly. You should keep this point in mind as we will revisit it later on.