Genetic Engineering as a Tool to Test Hypotheses of Muscle Function and Fatigue

Experiments based on genetic engineering are increasingly being used to test physiological hypotheses. Genetic engineering methods, for example, are being used extensively to study muscle function and fatigue. One example is provided by research on the role of the phosphagen creatine phosphate. Because creatine phosphate in mammalian muscle can be mobilized extremely rapidly to make ATP at a high rate (see Table 8.1), physiologists have long hypothesized that the phosphagen serves as a principal source of ATP during the first seconds of burst exercise. ATP synthesis from creatine phosphate depends on the enzyme creatine kinase (CK) (see Figure 8.7B). One way to test the hypothesis of phosphagen function is to lower or raise the levels of CK in muscle cells by genetic engineering methods. If the hypothesized role of creatine phosphate in burst exercise is correct, lowering or raising the levels of CK should interfere with or facilitate burst exercise.

Creatine kinase (CK)

Mutant mice deficient in CK have been reared by genetic engineering methods (see page 83 of the textbook). The muscles of these mice clearly exhibit compensatory adjustments that tend to make up for the effects of their CK deficiency. Even with such compensations, however, the muscles exhibit a subnormal ability to perform burst activity, and this performance deficit increases with the extent of their CK deficiency. Mice have also been engineered to produce unusually high amounts of CK. Their muscles contract faster than normal muscles in the first moments of isometric twitches. These experiments support the hypothesized role of creatine phosphate in burst exercise.

A second example of genetic engineering methods being used to study muscles is provided by studies on the potential role of high ADP concentrations in fatigue. These studies employed mice in which the gene for adenylate kinase was knocked out (see page 83 of the textbook). Muscles in such mice have normal ATP concentrations but develop exceptionally high ADP concentrations. The muscles were found, however, not to differ from ordinary muscles in the rate at which they develop fatigue during a long series of contractions. This result indicates that changes in intracellular ADP levels during exercise do not directly cause loss of contractile performance.