Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy

Abstract

Degenerative Cervical Myelopathy (DCM) is a progressive neurological condition characterized by structural alterations in the cervical spine, resulting in compression of the spinal cord. While clinical manifestations of DCM are well-documented, numerous unanswered questions persist at the molecular and cellular levels. In this study, we sought to investigate the neuromotor axis during DCM. We use a clinically relevant mouse model, where after 3 months of DCM induction, the sensorimotor tests revealed a significant reduction in both locomotor activity and muscle strength compared to the control group. Immunohistochemical analyses showed alterations in the gross anatomy of the cervical spinal cord segment after DCM. These changes were concomitant with the loss of motoneurons and a decrease in the number of excitatory synaptic inputs within the spinal cord. Additionally, the DCM group exhibited a reduction in the endplate surface, which correlated with diminished presynaptic axon endings in the supraspinous muscles. Furthermore, the biceps brachii (BB) muscle exhibited signs of atrophy and impaired regenerative capacity, which inversely correlated with the transversal area of remnants of muscle fibers. Additionally, metabolic assessments in BB muscle indicated an increased proportion of oxidative skeletal muscle fibers. In line with the link between neuromotor disorders and gut alterations, DCM mice displayed smaller mucin granules in the mucosa layer without damage to the epithelial barrier in the colon. Notably, a shift in the abundance of microbiota phylum profiles reveals an elevated Firmicutes-to-Bacteroidetes ratio-a consistent hallmark of dysbiosis that correlates with alterations in gut microbiota-derived metabolites. Additionally, treatment with short-chain fatty acids stimulated the differentiation of the motoneuron-like NSC34 cell line. These findings shed light on the multifaceted nature of DCM, resembling a synaptopathy that disrupts cellular communication within the neuromotor axis while concurrently exerting influence on other systems. Notably, the colon emerges as a focal point, experiencing substantial perturbations in both mucosal barrier integrity and the delicate balance of intestinal microbiota.

Keywords: Degenerative Cervical Myelopathy; motoneuron; muscle; neuromuscular; spinal cord; synapse.