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The craniosacral progression of muscle development influences the emergence of neuromuscular junction alterations in a severe murine model for spinal muscular atrophy
Author(s) -
Voigt Tilman,
Neve Anuja,
Schümperli Daniel
Publication year - 2014
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12064
Subject(s) - neuromuscular junction , anatomy , sma* , basal lamina , diaphragm (acoustics) , spinal muscular atrophy , biology , atrophy , muscle atrophy , muscle contracture , desmin , myocyte , pathology , medicine , neuroscience , skeletal muscle , microbiology and biotechnology , immunohistochemistry , ultrastructure , vimentin , physics , mathematics , disease , combinatorics , acoustics , loudspeaker
Aims As 4‐day‐old mice of the severe spinal muscular atrophy ( SMA ) model (dying at 5–8 days) display pronounced neuromuscular changes in the diaphragm but not the soleus muscle, we wanted to gain more insight into the relationship between muscle development and the emergence of pathological changes and additionally to analyse intercostal muscles which are affected in human SMA . Methods Structures of muscle fibres and neuromuscular junctions ( NMJs ) of the diaphragm, intercostal and calf muscles of prenatal ( E 21) and postnatal ( P 0 and P 4) healthy and SMA mice were analysed by light and transmission electron microscopy. NMJ innervation was studied by whole mount immunofluorescence in diaphragms of P 4 mice. Results During this period, the investigated muscles still show a significant neck‐to‐tail developmental gradient. The diaphragm and calf muscles are most and least advanced, respectively, with respect to muscle fibre fusion and differentiation. The number and depth of subsynaptic folds increases, and perisynaptic S chwann cells ( PSCs ) acquire a basal lamina on their outer surface. Subsynaptic folds are connected to an extensive network of tubules and beaded caveolae, reminiscent of the T system in adult muscle. Interestingly, intercostal muscles from P 4 SMA mice show weaker pathological involvement (that is, vacuolization of PSCs and perineurial cells) than those previously described by us for the diaphragm, whereas calf muscles show no pathological changes. Conclusion SMA ‐related alterations appear to occur only when the muscles have reached a certain developmental maturity. Moreover, glial cells, in particular PSCs , play an important role in SMA pathogenesis.