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 Bcl2/Bcl-X_L expression in skeletal muscle from fetuses with type I SMA (at ∼12 and 15 weeks' gestational ages, n = 4) and controls (at ∼10-15 weeks' gestational ages, n = 7). Myotubes were smaller in the SMA than in control samples at all agesanalyzed (p< 0.001) and were often arranged in clusters close toisolated 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 undergodifferent pathogenetic processes in SMA during development; they imply that muscle as well as motor neurons may be targets for early therapeutic intervention in SMA.