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

Abstract

Huntington's disease (HD) is a disorder characterized by chronic involuntary movements, dementia, and psychiatric symptoms. It is caused by a mutation in the gene that encodes for huntingtin protein (HTT), leading to the formation of mutant proteins expressed in various tissues. Although brain pathology has become the hallmark for HD, recent studies suggest that damage of peripheral structures also contributes to HD progression. We previously identified severe alterations in the motor units that innervate cervical muscles in 12-month-old BACHD (Bacterial Artificial Chromosome Huntington's Disease) mice, a well-established mouse model for HD. Here, we studied lumbar motoneurons and their projections onto hind limb fast-twitch skeletal muscles (tibialis anterior), which control balance and gait in HD patients. We found that lumbar motoneurons were altered in the HD mouse model; the number and size of lumbar motoneurons were reduced in BACHD. Structural alterations were also present in the sciatic nerve and neuromuscular junctions. Acetylcholine receptors were organized in several small patches (acetylcholine receptor fragmentation), many of which were partially innervated. In BACHD mice, we observed atrophy of tibialis anterior muscles, decreased expression of glycolytic fast Type IIB fibers, and at the ultrastructural level, alterations of sarcomeres and mitochondria. Corroborating all these findings, BACHD animals performed worse on motor behavior tests. Our results provide additional evidences that nerve-muscle communication is impaired in HD and that motoneurons from distinct spinal cord locations are similarly affected in the disease.

Neuroprotective effect of CTK 01512‐2 recombinant toxin at the spinal cord in a model of Huntington's disease

“…By decreasing the excessive exposure to glutamate, its excitotoxicity can be modulated (Doble, 1999), resulting in a reduction of the caspase-mediated apoptosis, hence preventing neuronal death. In a previous study, we showed that the BACHD spinal cord motoneurons are atrophic (Valadão et al, 2017(Valadão et al, , 2019 and, possibly, die after significant activation of caspase-3. Here, we confirmed caspase-3 activation and found that CTK 01512-2 was able to reduce the apoptosis of the spinal cord neurons.…”

“…The number of images and the total area investigated are given in the figure legend for each experiment. For muscle fibre analyses, the sternomastoideus (STM) and tibialis anterior (TA) skeletal muscles were removed and processed according to the protocol previously published (Valadão et al, 2017(Valadão et al, , 2019 (n = 5 animals per group, per treatment). We chose STM and TA because STM is innervated by motoneurons mostly from the cervical portion of the spinal cord and TA by motoneurons from the lumbar segment.…”

“…Both events have been associated with the progressive neuronal loss described for this condition (Creus‐Muncunill & Ehrlich, 2019; Hutten & Dormann, 2020; Ross & Tabrizi, 2011; Zaman et al., 2019). The main brain regions affected in HD are the striatum and cortex (Margolis & Ross, 2003); however, recent reports have described several alterations in the spinal cord, neuromuscular junctions, skeletal and cardiac muscles in an HD‐transgenic mouse model, the BACHD Q97 (BACHD) mouse (de Aragão et al., 2016; Joviano‐Santos et al., 2019; Valadão et al., 2017; Valadão et al., 2018; Valadão et al., 2019). The BACHD mouse expresses the human mutant HTT and presents slow disease progression, therefore being a valuable and unique model for investigating HD (Gray et al., 2008).…”

Skeletal Muscle Pathogenesis in Polyglutamine Diseases

“…HD muscle atrophy can result from the degeneration of different components of the motor unit, including the myofiber and the innervating motor neuron. Alteration of cervical and lumbar motor neurons was observed in HD mice [53][54][55]. Nonetheless, abnormalities were also detected in HD patient-derived muscle cells cultured in vitro, suggesting that some of the pathological features observed in vivo are cell-autonomous [56].…”

Purine Nucleotides Metabolism and Signaling in Huntington’s Disease: Search for a Target for Novel Therapies

“…At the cellular level, aggregation of mHTT, the inclusion of poly-ubiquitinated proteins were found in myofibers and myonuclei in R6/2 mice [ 9 , 71 ]. The mHTT formation in skeletal muscle leads to defects, such as myofiber size reduction, type switching, and denervation [ 69 , 72 , 73 , 74 , 75 ]. In addition to changes in myofiber structure, transcriptional deregulation, and deteriorations in energy metabolism occur linked to impaired adenine nucleotide metabolism [ 76 ].…”