Neuromuscular synapse degeneration without muscle function loss in the diaphragm of a murine model for Huntington's Disease

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by chorea, incoordination and psychiatric and behavioral symptoms. The leading cause of death in HD patients is aspiration pneumonia, associated with respiratory dysfunction, decreased respiratory muscle strength and dysphagia. Although most of the motor symptoms are derived from alterations in the central nervous system, some might be associated with changes in the components of motor units (MU). To explore this hypothesis, we evaluated morphofunctional aspects of the diaphragm muscle in a mouse model for HD (BACHD). We showed that the axons of the phrenic nerves were not affected in 12-months-old BACHD mice, but the axon terminals that form the neuromuscular junctions (NMJs) were more fragmented in these animals in comparison with the wild-type mice. In BACHD mice, the synaptic vesicles of the diaphragm NMJs presented a decreased exocytosis rate. Quantal content and quantal size were smaller and there was less synaptic depression whereas the estimated size of the readily releasable vesicle pool was not changed. At the ultrastructure level, the diaphragm NMJs of these mice presented fewer synaptic vesicles with flattened and oval shapes, which might be associated with the reduced expression of the vesicular acetylcholine transporter protein. Furthermore, mitochondria of the diaphragm muscle presented signs of degeneration in BACHD mice. Interestingly, despite all these cellular alterations, BACHD diaphragmatic function was not compromised, suggesting a higher resistance threshold of this muscle. A putative resistance mechanism may be protecting this vital muscle. Our data contribute to expanding the current understanding of the effects of mutated huntingtin in the neuromuscular synapse and the diaphragm muscle function.

Abnormalities in the Motor Unit of a Fast-Twitch Lower Limb Skeletal Muscle in Huntington’s Disease

“…Also, this age corresponds to middle age in humans, when it is supposed to appear HD symptoms. In addition, previous work from our research group have shown that 12-month-old BACHD mice present alterations in cardiac cells and other muscles such as STM and diaphragm (Valadão et al, 2017(Valadão et al, , 2018Joviano-Santos et al, 2019).…”

“…However, we judge that a study using females would be valuable, as HD is a disease that affects both sexes and it has already been shown that this disease has slightly faster progression in females than in males (Zielonka et al., 2013). In addition, in a recent study, Zielonka et al. (2018), showed that women with HD have a declining motor function affecting, more severely, on functionality and independence than in men.…”

“…Furthermore, marked muscle atrophy and fiber-type switching were observed in BACHD-sternomastoid (STM) muscles (Valadão et al, 2017). In addition, we also described abnormal NMJs in the diaphragm of BACHD mice (Valadão et al, 2018). Nonetheless, the hypothesis that HD may have a more direct connection with progressive disruption of communication between motoneurons and skeletal muscles remains poorly explored.…”

A suitable murine model for studying respiratory coronavirus infection and therapeutic countermeasures in BSL-2 laboratories

“…Whole-mount diaphragms were used to evaluate changes in NMJs of MHV-3-infected mice and mock controls. Sample processing and labeling of NMJs were performed based on a previous protocol (49). The pre-synaptic and post-synaptic terminals were stained using the monoclonal anti-synaptotagmin antibody (1:250 dilution, Developmental Studies Hybridoma Bank; cat No.…”

Efeito do treinamento muscular respiratório em pacientes com doença de Huntington: relato de casos

“…Conclusion: We concluded that respiratory muscle training may be beneficial for patients with Huntington's disease, but further studies are needed to determine the best protocol for them. Keywords: Huntington's disease, muscle strength, respiratory muscles, walk test, muscle trainning Introdução A Doença de Huntington (DH) é uma doença neurodegerenativa hereditária, caracterizada por alterações motoras, distúrbios psiquiátricos e disfunção cognitiva, causada por expansão do códon CAG (≥37 repetições) do gene de Huntington (IT15), expressa no braço curto do cromossomo 4, cujo início dos sintomas ocorre, geralmente, entre a quarta e quinta década de vida [1].…”