Neuromuscular junctions (NMJ) seem to play a more protagonistic role as initially thought in the pathophysiology of spinal muscular atrophy (SMA), according to a study recently published in Acta Neuropathologica Communications.

“We propose a model in which the dynamic communicative relationship between the motor neuron and muscle, along with the developmental subtype of the muscle, promotes motor unit subtype-specific vulnerability, metabolic alterations, and NMJ pathology,” the authors of the study wrote.

The experimental research included 2 different models of mice with spinal and bulbar muscular atrophy in determining the involvement of NMJ pathology in the fast-twitch muscle fibers impairment, characteristic of this disease. The authors registered the glycolytic-to-oxidative fiber-type switching and alterations of the cytoskeleton in both pre and postsynaptic termini of 3 muscles of the lower limb: the gastrocnemius, soleus, and tibialis anterior.

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“We observed significantly increased NMJ and myofber pathology in fast-twitch, glycolytic motor units of the TA and gastrocnemius compared to slow-twitch, oxidative motor units of the soleus, as seen by decreased pre- and post-synaptic membrane area, decreased pre- and post-synaptic membrane colocalization, increased acetylcholine receptor compactness, a decrease in endplate area and complexity, and deficits in neurofilament heavy chain,” Molostky and colleagues reported.

Although NMJ dysfunction is a known event in SMA, its precise significance has not yet been defined. The differences observed in NMJ pathology among fast- and slow-twitching muscles coincide with typical findings of this disease.

Nonetheless, these results further demonstrated that NMJ alterations were exclusive to the postsynaptic membranes in the tibialis anterior, as opposed to the gastrocnemius, which also included the presynaptic membrane. The study explains that this phenomenon could be secondary to differing features during development, such as the fast synapse of tibialis anterior vs delayed synapse of gastrocnemius and soleus during acetylcholine receptor clustering.

Acknowledging these novel physiological characteristics involving neuromuscular synapses reported in this study may become a topic of interest to determine better and possibly even prevent disease progression in spinal and bulbar muscular atrophy.


Molotsky E, Liu Y, Lieberman A, Merry D. Neuromuscular junction pathology is correlated with differential motor unit vulnerability in spinal and bulbar muscular atrophy. Acta Neuropathol Commun. Published online July 5, 2022. doi:10.1186/s40478-022-01402-y