On the possible role of muscle in the pathogenesis of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a common human inherited disease character ized by degeneration of motoneurons and muscular atrophy. SMA results from deletions or mutations of the SMN (survival motor neuron) gene. A nerve-mus cle coculture model, consisting of human muscle cells innervated by rat emb ryonic spinal cord explants, was used to study the pathogenesis of SMA. Pre vious studies have shown that myotubes formed by fusion of satellite muscle cells from patients with SMA I or SMA II rout not SMA III) underwent a cha racteristic degeneration 1-3 weeks after innervation, To correlate this cel lular study with a molecular approach, we used reverse transcriptase-polyme rase chain reaction (RT-PCR), and showed that SMN mRNAs were expressed thro ughout the fusion of normal satellite muscle cells with two peaks, the firs t appearing prior to the onset of fusion and the second one or two days bef ore innervation. When satellite muscle cells from patients with SMA I or II were used, only the first peak was observed, Because in these cases the SM N telomeric gene (SMNtel) is deleted, it was concluded that the contributio n of SMNtel-dependent mRNAs to tile second peak is predominant in normal my ogenesis and involved in maturation of myotubes, In addition, diseased sate llite muscle cells did not fuse at the same rate as normal satellite muscle cells. Studies on myf-5, a muscle specific transcription factor family, sh owed that its expression was impaired during the fusion of satellite muscle cells from patients with SMA I or II compared with normal satellite muscle cells. Taken together, these observations suggest that (a) there is a musc le specific expression pattern of SMN, and (b) SMN probably plays a crucial role in maintenance of a functional motor unit, by allowing muscle cells t o correctly differentiate and to allow motoneuron survival.