Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA)

Abstract

Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient levels of the survival motor neuron (SMN) protein. One of the most prominent pathological characteristics of SMA involves defects of the neuromuscular junction (NMJ), such as denervation and reduced clustering of acetylcholine receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce muscle atrophy in the delta7 mouse model of SMA. To test whether the muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly improved innervation and synaptic efficacy in denervation-vulnerable muscles. MuSK agonist antibody #13 also significantly increased the muscle cross-sectional area and myofiber numbers in these denervation-vulnerable muscles but not in denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect the body weight, our study suggests that preservation of NMJ innervation by the activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to maximize the therapeutic effectiveness for all types of SMA patients.

Neuromuscular denervation and deafferentation but not motor neuron death are disease features in the Smn2B/- mouse model of SMA

“…They are also consistent with the preferential susceptibility to NMJ denervation of proximal and axial SMA muscles that is observed across mouse models and appears more pronounced in SMND7 mice [37,40,50,51]. Lastly, the loss of NMJs from the QL muscle without death of the corresponding innervating motor neurons corroborates the conclusion that these two key pathogenic events are mechanistically uncoupled in SMA [28,29,[52][53][54].…”

Neuromuscular denervation and deafferentation but not motor neuron death are disease features in the Smn2B/- mouse model of SMA

“…They are also consistent with the preferential susceptibility to NMJ denervation of proximal and axial SMA muscles that is observed across mouse models and appears more pronounced in SMNΔ7 mice [38,41,51,52]. Lastly, the loss of NMJs from the QL muscle without death of the corresponding innervating motor neurons corroborates the conclusion that these two key pathogenic events are mechanistically uncoupled in SMA [28,29,[53][54][55]. Interestingly, dissociation of motor neuron death from NMJ denervation has also been observed in a mouse model of amyotrophic lateral sclerosis [56].…”

“…Interestingly, dissociation of motor neuron death from NMJ denervation has also been observed in a mouse model of amyotrophic lateral sclerosis [56]. Future studies are required to establish whether the same RNA-mediated mechanisms of NMJ denervation identified in SMNΔ7 mice are at play in in Smn 2B/mice [53][54][55].…”

Denervation-Related Neuromuscular Junction Changes: From Degeneration to Regeneration

“…To reduce the inflammation response, McAvoy et al (2019) developed a microelectrode array which successfully stabilize the AchRs during long-term denervation. As discussed before, Agrin-LRP4P-MuSK signaling can be important for the maintenance of NMJs, therapy-targeting MuSK, which is thought to be of great clinical value, has been attempted to preserve NMJ ( Cantor et al, 2018 ; Feng et al, 2021 ). However, most studies focusing on these therapeutic medicines are still limited in the animal trials stage.…”