Genioglossus sarcomere and mitochondria morphology in a rodent model of hypoglossal motor neuron death

Upper airway dysfunction in motor neuron diseases, such as amyotrophic lateral sclerosis and progressive muscular atrophy, is largely attributed to degeneration of hypoglossal (XII) lower motor neurons (LMNs) which innervate the genioglossus muscle of the tongue and often results in progressive tongue weakness. A barrier in studying the impact of XII LMN degeneration and developing therapies to improve swallowing and breathing function/coordination has been the lack of an appropriate model. We developed a novel rodent model using intralingual injections of cholera toxin B conjugated to saporin (CTB-SAP) to induce targeted loss of XII LMNs and XII motor output. Prior work with this model revealed degenerative changes in the genioglossus ( e.g., genioglossus myofiber atrophy which is replaced by increased lipid expression to lead to overall tongue hypertrophy) as well as decreased tongue motility and swallowing deficits. However, ultrastructural genioglossal myofiber changes ( e.g., sarcomere and mitochondria morphology) in response to induced XII LMN death in CTB-SAP rats remain unknown. We hypothesize that XII LMN loss leads to degenerative changes in genioglossus sarcomere and mitochondria morphology in CTB-SAP rats. Here, we intralingually injected adult male rats with CTB-SAP or control (CTB unconjugated to SAP) and studied ultrastructural changes in genioglossus sarcomere and mitochondria morphology using transmission electron microscopy and computational methods as well as machine learning. Our preliminary data suggests a dysregulation of sarcomere ultrastructure, particularly Z-lines, and a significant increase in mitochondrial perimeter and maximum Feret’s diameter in CTB-SAP rats vs. controls (both n=3; p<0.05), consistent with degenerative changes and a potential inflammatory response in genioglossus muscle cells following the loss of XII LMNs. We are now analyzing genioglossus lipid droplet and glycogen densities across groups. Better characterizing and understanding the impact of XII LMN loss on genioglossus ultrastructural changes will allow us to better design therapeutic strategies to mitigate deficits in upper airway function in patients with motor neuron diseases. Sponsored by: NSF Computational Neuroscience grant and NIH R01 HL153612 grant This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.