Introduction

Skeletal muscle has a highly variable requirement for energy (in the form of ATP) depending on the demand placed on the muscle. Potentially, this energy can be derived from a variety of sources. However, during severe exercise when the energy demand is very high, blood is squeezed out of the muscle bed by contractile activity. The muscle is then temporarily starved of oxygen (becomes ischemic), making oxidative processes very difficult. In these circumstances, oxidation of fatty acids, normally the most efficient means of generating energy, cannot be relied upon to satisfy the large energy demand. Instead the muscle has to depend more heavily on anaerobic glycolysis. Even here the muscle faces problems since the diminished blood flow prevents glucose being imported to fuel glycolysis so the muscle's glycogen stores must be mobilized. In addition, the end product of anaerobic glycolysis, lactate, cannot be removed efficiently via the blood and has to accumulate within the muscle. As a consequence, humans cannot carry out severe ischemic exercise for more than a few minutes, as athletes will know only too well.

Comparatively rarely, individuals are encountered who, because of a genetic defect, cannot tolerate ischemic exercise. The problem features such an individual.

The Problem

Phillip M., a sixteen-year-old boy, sought medical help for progressive muscle weakness over a number of years. He experienced painful muscle cramps on severe exercise but he could tolerate moderate exercise normally. The effect of sever ischemic exercise on blood lactate is shown in Figure 1. Sever exercise was followed by dramatically elevated serum levels of lactate dehydrogenase, creatine kinase and aldolase, which persisted for some hours after exercise had ceased. Myoglobinurea was also present and there was evidence of mild hemolysis. Phillip's blood glucose level was normal and could be elevated by treatment with glucagon. It was decided to do a muscle biopsy. Table 1 shows the results of the biopsy analysis.

Questions

1. Why is lactate, rather than pyruvate, produced by normal muscle when it is working anaerobically?
2. What do the results of the ischemic exercise test suggest is wrong with Philip's muscles?
3. How does glucagon act and what do the results of treating Phillip with glucagon indicate about his condition?
4. What can you conclude from the muscle biopsy analysis?
5. From your deductions so far, what do you think is the metabolic defect in the patient?
6. Why is Phillip able to tolerate moderate, but not sever, exercise?
7. What is the significance of his serum enzyme levels and the myoglobinuria?
8. Why is there an increased deposition of muscle glycogen (Table 1)?
9. What evidence might have been present to support the suggestion of hemolysis? How does it arise in this patient?

Connections

• Draw outline schemes for the processes of glycolysis, gluconeogenesis, glycogenesis (glycogen synthesis) and glycogenolysis (glycogen breakdown). Fit these processes together and explain the mechanisms which ensure that the synthetic and degradative pathways do not operate simultaneously.
• Review the glycogen storage disorders, their biochemistry, the medical symptoms and the prognoses.
• List the different processes whereby ATP may be regenerated by phosphorylation of ADP. What type of phosphorylation is involved in the production of ATP in anaerobic glycolysis and at which points in the pathway is ATP produced? What is the significance of creatine kinase in muscle?
• Use this problem to review your knowledge of how insulin and glucagon influence carbohydrate metabolism and the different roles played by liver and muscle glycogen.
• Check that you understand what jaundice is and the different ways in which it may arise.
• Think of ways in which enzymes can be used as diagnostic tools or therapeutic reagents.

* This Case study is taken from Higgins, S.J., Turner, A.J. and Wood, E.J., Biochemistry for the Medical Sciences., Longman Scientific and Technical, 1994.