Neuromuscular Junction Morphology and Gene Dysregulation in the Wobbler Model of Spinal Neurodegeneration
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Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disease for which there is currently no effective treatment. The progression of ALS includes loss of motor neurons controlling the voluntary muscles, with much of this loss occurring at the neuromuscular junction. In an effort to better understand changes at the neuromuscular junction, we utilized the wobbler mouse model of motor neuron loss. We examined biceps and end plate morphologies and monitored selected factors involved in end plate function. Structural volumes were determined from 3D reconstructions that were generated for the end plates. Wobbler mice exhibited size reductions of both the muscle fibers and the end plates within the biceps, and we found that the end plate volumes were the most sensitive indicator of the degeneration. Concurrently, we found increases in calcitonin gene-related peptide (CGRP) and its receptor in wobbler biceps and spinal cord. We also found increases in gene expression of two acetylcholine receptors within the wobbler biceps, which may be a result of altered CGRP/CALCRL (calcitonin receptor-like receptor) expression.
KeywordsNeuromuscular junction End plate Calcitonin gene-related peptide (CGRP) Motor neuron disease Wobbler mice
This article is dedicated to the memories of Drs. Hugo L. Fernandez and Irving Nadelhaft, instrumental in this field, and wonderful colleagues. We thank Haris Hatic, Andrea Smith, and John S. Dennis for excellent technical assistance. Useful, early discussions were obtained from Irving Nadelhaft and Hugo Fernandez.
This study was supported by the Department of Veterans Affairs (Veterans Health Administration, Office of Research and Development, Rehabilitation Research and Development (I01RX001520)), the Assistant Secretary of Defense for Health Affairs through the Congressionally Directed Gulf War Illness Research Program (W81XWH-16-1-0626), the Florida Department of Health James and Esther King Biomedical Research Program (4KB14), The Bay Pines Foundation, and the Veterans Bio-Medical Research Institute.
Compliance with Ethical Standards
All experiments were performed in accordance with local and national guidelines.
The contents do not represent the views of the Department of Veterans Affairs or the US Government, and the opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.
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