Muscles fatigue when there is not sufficient blood flow to transport oxygen and maintain aerobic respiration.
Oxidation of fats requires more oxygen than oxidation of glucose, and the increased use of fat during exercise increases the problem if oxygen shortage.
When there is insufficient oxygen, respiration becomes anaerobic, lactic acid accumulates, and increased acidity contributes to fatigue. It inhibits resynthesis of phospho creatine and interferes with actin/myosin crossbridge formation, possibly by interfering with the binding of calcium ions to troponin.
It also inhibits enzymes, especially those involved in glycolysis and decreases the amount of energy released by the hydrolysis of ATP.
From Colin Clegg (1995) - "Exercise physiology and functional anatomy", Feltham Press
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