Muscle fatigue refers to the decline in a muscle's ability to maintain the force of contraction after prolonged activity. It primarily stems from changes within muscle fibers. Even before experiencing muscle fatigue, one may feel tired and have the urge to stop the activity. This response, known as central fatigue, occurs due to changes in the central nervous system, namely the brain and spinal cord. While there is no single mechanism that induces fatigue, it may serve as a protective response to prevent muscle damage that can be caused due to overuse.

During intense or prolonged physical activity, the ATP demand in the muscles increases. As contractions become more vigorous, compressed blood vessels hinder the oxygen supply to the tissues. Consequently, muscles resort to anaerobic glycolysis to produce ATP, leading to the production of lactic acid. The accumulation of lactate and hydrogen ions from ATP hydrolysis adversely affects cellular pH, resulting in lactic acidosis, which hampers muscle contraction and leads to fatigue. To recover, muscles require time and ample oxygen to regenerate ATP. Once oxygen levels are restored, lactate dehydrogenase enzymatically converts accumulated lactate back into pyruvate. Mitochondria then utilize pyruvate to produce more ATP or enzymatically convert it into glycogen for storage. The surplus ATP is utilized by the enzyme creatine kinase to replenish phosphocreatine reserves.

In addition, the muscles redirect any excess lactate to the liver. Once in the liver, the lactate converts back into glucose, which is then transported back to the muscles. This cyclic process, known as the Cori cycle, is a vital metabolic pathway that plays a crucial role in the transport and conversion of lactate. It ensures the efficient metabolism of lactate, thereby enabling sustained energy production in the body.