Characterization of intercostal muscle pathology in canine degenerative myelopathy: A disease model for amyotrophic lateral sclerosis

Abstract

Dogs homozygous for missense mutations in the SOD1 gene develop a late-onset neuromuscular disorder called degenerative myelopathy (DM) that has many similarities to amyotrophic lateral sclerosis (ALS). Both disorders are characterized by widespread progressive declines in motor functions accompanied by atrophic changes in the descending spinal cord tracts , and some forms of ALS are also associated with SOD1 mutations. In end-stage ALS, death usually occurs as a result of respiratory failure due to severe functional impairment of respiratory muscles. The mechanisms that lead to this loss of function are not known. Dogs with DM are euthanized at all stages of disease progression providing an opportunity to characterize the onset and progression of any pathological changes in the respiratory muscles that may precede respiratory failure. To characterize such potential disease-related pathology we evaluated intercostal muscles from Boxer and Pembroke Welsh Corgi dogs that were euthanized at various stages of DM disease progression. DM was found to result in intercostal muscle atrophy, fibrosis, increased variability in muscle fiber size and shape, and an alteration in muscle fiber type composition. This pathology was not accompanied by retraction of the motor neuron terminals from the muscle acetylcholine receptor complexes, suggesting that the muscle atrophy did not result from physical denervation. These findings provide a better understanding of the mechanisms that likely lead to respiratory failure in at least some forms of ALS and will be useful in the development and evaluation of potential therapeutic interventions using the DM model.

Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy

“…A presumptive clinical diagnosis is made by ruling out potential causes of compressive myelopathy; however, confirmation requires histopathological examination of the spinal cord (16). The pathological features of DM are similar to the pathological features of ALS (17)(18)(19)(20)(21)(22). DM has been confirmed in over 24 breeds (16,23) and presumptively reported in another nine breeds (16).…”

Characterization of thoracic motor and sensory neurons and spinal nerve roots in canine degenerative myelopathy, a potential disease model of amyotrophic lateral sclerosis

“…Clinical signs appear in pelvic limbs as spastic upper motor neuron (UMN) paresis and general proprioceptive ataxia, which progresses to flaccid tetraplegia and dysphagia if euthanasia is delayed (Coates and Wininger, ). As with some forms of familial amyotrophic lateral sclerosis (ALS), DM is associated with mutations in superoxide dismutase 1 ( SOD1 ; Andersen et al, ; Coates and Wininger, ; Morgan et al, ). DM occurs in many breeds and is typically accompanied by the SOD1 missense mutation SOD1:c.118G→A , which predicts a p.E40K substitution (Awano et al, ).…”

Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis

“…Results reported in the literature vary significantly according to muscle group and breed. There is another important discrepancy; some authors reported significant MN loss , while others reported no MN loss in the same breed and spinal segments (Morgan et al, 2013).…”

“…It is difficult to explain the reasons for this discrepancy using the available data, but ALS actually encompasses a spectrum of disorders, and it is possible that fiber type grouping occurs in some forms of the disease and not in others (Soraru et al, 2008). Since no fiber type grouping in intercostal muscles (Morgan et al, 2013) or in pelvic limb muscles (Shelton et al, 2012) has been identified in PWCs with late-stage CDM, it can be assumed that this breed replicates muscle pathology of only some forms of ALS muscle (Morgan et al, 2013). A markedly increased ratio of type 1 to type 2 fibers seen in end-stage PWCs, relative to that in a normal PWC, has also been reported in hind limb muscles from an ALS mouse model with a low copy number of a mutant SOD1 transgene (Acevedo-Arozena et al, 2011).…”

“…The results of a recent neuropathological study (Morgan et al, 2013) indicate that this atrophy can be observed in the intercostal muscles of dogs that were euthanized at various stages of CDM progression. The CDM-related changes in muscle morphology are typical of those associated with denervation atrophy, suggesting a neurogenic pathology resulting from altered MN input to the muscle (Shelton et al, 2012).…”