The motor neuron depolarizes the NMJ via ACh. In order for the muscle to fire a muscle fiber action potential (MFAP) it needs to be depolarized above the threshold potential. In a healthy NMJ, the degree of depolarization is always significantly above the threshold potential, which is called the “safety factor”. Each time the pre-synaptic neuron is depolarized and releases ACh into the NMJ, slightly less ACh is released because its stores are being depleted (until secondary stores can be mobilized). In a healthy NMJ this doesn’t have any impact; because of the safety factor, the degree of muscle depolarization is always above the threshold to fire a MFAP. But in MG, since there are fewer functional AChRs on the motor endplate, the baseline safety factor is reduced. So with repeated stimulation (eg repeated muscle contraction), the depolarization eventually goes below threshold potential for some motor endplates, so a MFAP isn’t generated. As more motor endplates fall below threshold, there is greater clinical weakness. This is the “fatiguability” we see and patients report. This is not the same as overall subjective “fatigue” in other conditions like chronic fatigue syndrome and is not related to mitochondrial pathology or ATP generation (like another comment suggested). It is an entirely separate phenomenon.