Fatigue at the neuromuscular junction: Branch point vs. presynaptic vs. postsynaptic mechanisms

There are several pre- and postsynaptic sites where neuromuscular transmission failure (NTF) can occur, leading to peripheral muscle fatigue. Presynaptic sites of NTF include: axonal branch point conduction block; a failure of excitation-secretion coupling at the presynaptic terminal; reductions in quantal release of ACh; and reductions in quantal size. Postsynaptic sites of NTF include; cholinergic receptor desensitization; and reduced sarcolemmal excitability. Susceptibility to NTF increases with stimulation frequency and is most prevalent in fatigable fast-twitch motor units. In addition, susceptibility to NTF varies with age and with conditions of altered use.