Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.

Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

“…To determine whether dual treatment ameliorates the NMJ defects compared with MO E1v11 monotherapy, treatment groups were analyzed by immunofluorescent staining of the longissimus capitis muscle. This muscle was selected because prior studies have demonstrated that the longissimus capitis muscle is particularly sensitive and exhibits significant pathology with respect to NMJ maturation, denervation, and morphology in the SMNΔ7 mouse model (30). Both treatment groups resulted in visibly improved NMJ size and innervation compared with the untreated SMNΔ7 mouse ( Figure 5, A and B), as evidenced by the similar levels of fully innervated NMJs as well as the degree of partial and fully denervated end plates ( Figure 5C).…”

Muscle-Derived Extracellular Signal-Regulated Kinases 1 and 2 Are Required for the Maintenance of Adult Myofibers and Their Neuromuscular Junctions

“…Some are highly affected, while others appear to be resistant. In many cases, these muscle-selective effects include how their NMJs react to these conditions (40,72,73). The mechanisms underlying these unique sensitivities remain elusive and are likely to be complex and condition specific.…”

ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

“…This treatment concept has been validated in mouse models of SMA by several approaches including targeted transgenic expression of SMN1 in motor neurons, gene replacement with adeno-associated viruses, oligonucleotides that promote inclusion of exon 7, and histone deacetylase (HDAC) inhibitors that increase SMN expression (13)(14)(15). Additionally, SMA severity in human patients and SMA mouse models correlates with the number of SMN2 copies (16,17). Currently, there are about 18 therapeutic programs for SMA in various stages of preclinical and clinical development (18).…”