Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progress ive muscle weakness that affects muscles in an apparent proximal-to-distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA anima ls, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. Wk determined whether str uctural changes in neuromuscular junctions or muscle fibers were apparent a t: times when tetanic failure is prevalent. We were surprised to observe th at, at ages when motor unit tetanic failure is common, the structure of neu romuscular junctions and the appearance of muscle fibers in the MC; muscle were indistinguishable from those of symptom-free animals. In contrast, in more proximal muscles, many neuromuscular junctions were disassembled, with some postsynaptic specializations only partially occupied by motor nerve t erminals, and muscle fiber atrophy and degeneration were also apparent. The se observations suggest that the motor unit tetanic failure observed in the MG muscle in homozygous animals is not due to synaptic degeneration or to pathological processes that affect muscle fibers directly. Together with pr evious physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerv e or muscle degeneration.