Reorganization of the nuclear compartments involved in transcription and RNA processing in myonuclei of type I spinal muscular atrophy.

Abstract

Type I spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by the loss or mutation of the survival motor neuron 1 (SMN1) gene. The reduction in SMN protein levels in SMA leads to the degeneration of motor neurons and muscular atrophy. In this study, we analyzed the nuclear reorganization in human skeletal myofibers from a type I SMA patient carrying a deletion of exons 7 and 8 in the SMN1 gene and two SMN2 gene copies and showing reduced SMN protein levels in the muscle compared with those in control samples. The morphometric analysis of myofiber size revealed the coexistence of atrophic and hypertrophic myofibers in SMA samples. Compared with controls, both nuclear size and the nuclear shape factor were significantly reduced in SMA myonuclei. Nuclear reorganization in SMA myonuclei was characterized by extensive heterochromatinization, the aggregation of splicing factors in large interchromatin granule clusters, and nucleolar alterations with the accumulation of the granular component and a loss of fibrillar center/dense fibrillar component units. These nuclear alterations reflect a severe perturbation of global pre-mRNA transcription and splicing, as well as nucleolar dysfunction, in SMA myofibers. Moreover, the finding of similar nuclear reorganization in both atrophic and hypetrophic myofibers provides additional support that the SMN deficiency in SMA patients may primarily affect the skeletal myofibers.