title: Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease.
abstract: Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progressive muscle weakness that affects muscles in an apparent proximal-to-distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA animals, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. We determined whether structural changes in neuromuscular junctions or muscle fibers were apparent at times when tetanic failure is prevalent. We were surprised to observe that, at ages when motor unit tetanic failure is common, the structure of neuromuscular junctions and the appearance of muscle fibers in the MG 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 terminals, and muscle fiber atrophy and degeneration were also apparent. These 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 previous physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerve or muscle degeneration.
authors.affiliation: Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Balice-Gordon
authors.forename: D B
authors.initials: DB
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Goldman
authors.forename: L C
authors.initials: LC
authors.lastname: Cork
authors.forename: A
authors.initials: A
authors.lastname: Shirley
authors.forename: T C
authors.initials: TC
authors.lastname: Cope
authors.forename: M J
authors.initials: MJ
authors.lastname: Pinter
mesh_terms: D000818:Animals; D001369:Axons / Q000648:ultrastructure; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D016472:Motor Neuron Disease / Q000473:pathology* / Q000503:physiopathology; D018485:Muscle Fibers, Skeletal / Q000648:ultrastructure; D018908:Muscle Weakness / Q000209:etiology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000503:physiopathology / Q000648:ultrastructure; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D009410:Nerve Degeneration / Q000473:pathology; D009468:Neuromuscular Diseases / Q000473:pathology / Q000503:physiopathology; D009469:Neuromuscular Junction / Q000503:physiopathology; D011950:Receptors, Cholinergic / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000378:metabolism
chemical_list: D011950:Receptors, Cholinergic; D017661:Receptors, Presynaptic