Biochemistry of muscle fatigue

Fatigue--or decrease in force generation--is a reduction of simultaneously attached cross-bridges in the force generating state. Two processes are necessary for the force generation: Firstly Ca++ release from the sarcoplasmic reticulum to the sarcoplasm and the binding of Ca++ by the troponin molecule and secondly the turnover of myosin-actin cross-bridges. These processes require energy in at least three different ATPase reactions and can consequently be inhibited when ATP hydrolysis is decreased, i.e. when ATP content is to low or when the reaction products (ADP, Pi and H+) reach inhibiting levels or when muscle pH has decreased to values inhibiting actomyosin ATPase activity (22). Low pH will also decrease Ca++ release and Ca++ affinity by troponin (23). In isometric contraction the force is well preserved as long as ADP phosphorylation can be provided by both PCr degradation and anaerobic glycolysis. When the PCr store is exhausted the force starts to decline and if muscle activation is maintained the force will continue to decrease along with falling glycolytic rate. ADP phosphorylation rate decreases successively and ATP content falls with an at least transient increase in ADP. The ATP decrease, apart from the minor increase in ADP, is balanced by an equimolar increase in IMP. Lactate accumulation produces an increasing acidity with muscle pH values down to 6.25. Early changes in free ADP content cannot be excluded as reason for the initial decrease in force production followed by more pronounced inhibition of ATPase activity during continued contraction due to both substrate lack and product inhibition together with pH effect on the excitation--contraction mechanism. In dynamic exercise with supramaximum work intensity the relation between fatigue development and metabolism is similar. In prolonged dynamic exercise relying on oxidative metabolism without lactate formation the point of fatigue is reached when the glycogen store is exhausted. Again ADP phosphorylation rate is decreased when the energy substrate is changed from carbohydrate to fat with lower maximum rate of ATP resynthesis.