Pathophysiology of the Neuromuscular Junction

Normal Signalling

Nerves communicate with muscle fibers at a special synapse, the neuromuscular junction (NMJ). Here, the ends of the axon (synaptic end-bulbs) come very close to the membrane (sarcolemma) of the muscle fiber. The synaptic end-bulbs contain sacs (synaptic vesicles) filled with neurotransmitter. The neurotransmitter at the NMJ of skeletal muscles is always acetylcholine (Ach).

Notice how in the illustration the sarcolemma at the NMJ (the motor end-plate) is folded (junctional folds) and contains embedded proteins. These proteins have 2 functions; they serve as receptors for Ach and also serve as (gated) ion channels. When the nerve signal arrives at the end of the axon, the synaptic vesicles move towards the synapse and break open, releasing Ach which diffuses across the synaptic cleft and binds to the receptor.

As seen in the illustration below, binding of Ach to the receptor has the effect of changing the shape of the protein, causing the channel to open. The channel allows positively charged ions (mainly sodium = Na⁺) to move across. The effect of this is depolarization of the muscle fiber membrane, initiating a series of events that lead to muscle contraction. An enzyme within the synapse, acetylcholinesterase (AchE), degrades Ach into acetate and choline. This allows for cessation of the signal and relaxation of the muscle.

Effects of Toxins

             Exposure to certain chemicals can impair signalling at the NMJ. Botulinum toxin is produced by the bacterium Claustridium botulinum. The specific effect of this toxin is prevention of exocytosis (release) of synaptic vesicles, thereby preventing signalling by Ach. As can be seen in this image, the toxin cleaves proteins that normally transport the synaptic vesicle towards the synapse. Botulinum toxin (Botox) is used cosmetically and has a number of other therapeutic applications.

               VX (venomous agent X) nerve agent is a deadly toxin that impairs signalling at the NMJ. This agent, along with sarin nerve gas, impairs degradation of acetylcholinesterase within the synapse. As seen in this image, this increases the amount and duration of Ach in the synapse, leading to unregulated contraction of skeletal and smooth muscle (including bronchioles in the lungs).

Genetic Effects

               Dystrophin is a protein that is critical for linkage of the sarcolemma to protein (actin) fibers within the muscle fiber. Duchenne muscular dystrophy is a genetic disorder in which absence of the dystrophin protein has profound effects on formation of NMJ. These include abnormal junctional folds and reduced expression of Ach receptors. This results in impaired signalling across the synapse, contributing to the muscle weakness and wasting characteristic of the disease.

Immune System Effects

Myasthenia gravis is an autoimmune disorder in which the body produces antibodies (autoantibodies) that recognize and attack the acetylcholine receptor. The main pathogenic pathway involves binding of autoantibodies to the receptor and subsequent immune activation (complement system). The activated complement system attacks and degrades the postsynaptic membrane. Overall, the effect is impaired signalling at the NMJ and progressive weakness of skeletal muscles that control functions including: eye movement, speech, eating, breathing, and limb movements. Myasthenia gravis can be treated with acetylcholinesterase inhibitors that enhance signalling across the NMJ.

Effects of Activity and Age

The NMJ is continuously remodelled and a number of factors can influence this process. Age-related reduction in muscle function has been linked to age-related changes in the muscle fibers themselves and to changes in the motor neurons that supply the muscle (and both of these can have adverse effects on the NMJ). These processes are thought to drive progressive, age-related loss of muscle mass and muscle weakness (called sarcopenia). In contrast, it is thought that age-related degeneration at the NMJ can be reduced by exercise.  Interestingly, in animal studies, these effects varied according to the type of exercise (endurance versus resistance).