title: The developmental pattern of myotubes in spinal muscular atrophy indicates prenatal delay of muscle maturation.
abstract: The loss and degeneration of spinal cord motor neurons result in muscle denervation in spinal muscular atrophy (SMA), but whether there are primary pathogenetic abnormalities of muscle in SMA is not known. We previously detected increased DNA fragmentation and downregulation of Bcl-2 and Bcl-X(L) expression but no morphological changes in spinal motor neurons of SMA fetuses. Here, we performed histological and morphometric analysis of myotubes and assessed DNA fragmentation and Bcl-2/Bcl-X(L) expression in skeletal muscle from fetuses with type I SMA (at approximately 12 and 15 weeks' gestational ages, n = 4) and controls (at approximately 10-15 weeks' gestational ages, n = 7). Myotubes were smaller in the SMA than in control samples at all ages analyzed (p < 0.001) and were often arranged in clusters close to isolated and larger myotubes. Numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells in control and SMA fetuses were similar, and no differences in Bcl-2 or Bcl-X(L) immunostaining between control and SMA muscle were identified. Areas with smaller myotubes and the morphometric analysis suggested a delay in growth and maturation in SMA muscle. These results suggest that spinal motor neurons and skeletal muscle undergo different pathogenetic processes in SMA during development; they imply that muscle as well as motor neurons may be targets for early therapeutic intervention in SMA.
authors.affiliation: Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Martínez-Hernández
authors.forename: Carolina
authors.initials: C
authors.lastname: Soler-Botija
authors.forename: Eva
authors.initials: E
authors.lastname: Also
authors.forename: Laura
authors.initials: L
authors.lastname: Alias
authors.forename: Lidia
authors.initials: L
authors.lastname: Caselles
authors.forename: Ignasi
authors.initials: I
authors.lastname: Gich
authors.forename: Sara
authors.initials: S
authors.lastname: Bernal
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Tizzano
mesh_terms: D000367:Age Factors; D053938:DNA Fragmentation; D005333:Fetus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013116:Spinal Cord / Q000196:embryology / Q000378:metabolism / Q000473:pathology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2