This important study showed that creatine supplementation can reduce post-workout fatigue by reducing the supraspinal CNS fatigue caused by inflammatory mediators produced in response to the presence of muscle damage. This would allow damaged muscle to be more readily activated during maximal efforts in subsequent workouts.

Creatine supplementation appears to accelerate recovery from post-workout fatigue by acting on the secondary muscle damage effect. This suggests that it works by an anti-inflammatory or anti-oxidant mechanism. Typically, interfering with the muscle damage repair process is not a great idea, since it can impair future muscle fiber adaptations. Whether this happens with creatine is unclear, however.

Severe caloric restriction causes a dramatic reduction in muscle glycogen, which could then trigger fatigue mechanisms like supraspinal CNS fatigue and excitation-contraction coupling during exercise, reducing adaptations from workouts.

Sleep loss is known to affect workout performance negatively. It does this by increasing pain sensitivity, which reduces our ability to produce maximum levels of motor unit recruitment by reducing the maximum tolerable perception of effort.

Acidosis is a metabolite-related fatigue mechanism. Exercise training can reduce the rate at which acidosis develops by a variety of adaptations. One such adaptation is an increase in extracellular (outside the muscle fiber) buffering capacity.