According to Physiology.org, skeletal muscle fatigue is caused by the intense and repeated use of muscles without a healthy amount of rest between workouts or strenuous events. Wikipedia states that ATP is a molecular substrate within the muscle also known as adenosine triphosphate; these substrates are depleted during exercise. Muscle fatigue is most often caused by a substrate shortage. Resting helps replenish these substrates.
Wikipedia explains that skeletal muscle fatigue is an uncomfortable but temporary condition that many active adults have to deal with. Generally, skeletal muscle fatigue is caused by strenuous exercise, but it can also have a biological cause. High potassium is one of these biological causes, according to Wikipedia. When the human body has too much potassium in its system, the muscle cells are not as efficient, leading to fatigue and cramping.
Wikipedia also explains that lactic acid is another possible cause of muscle fatigue, though the exact impact lactic acid build-up has on muscle performance is uncertain. If someone is suffering from skeletal muscle fatigue, blood work is needed to ensure that the problem is related to exercise instead of nutrition imbalances caused by a poor diet. Physiology.org states that rest is the best treatment for skeletal muscle fatigue.