Abnormal expression of myosin heavy chains in early postnatal stages of spinal muscular atrophy type I at single fibre level

Objectives. We investigated myosin heavy chain (MyHC) isoform expression at early postnatal stag- es of clinically and genetically confirmed spinal muscular atrophy type 1 (SMA1) patients, in order to study the muscle fibre differentiation compared to age-matched controls at single fibre level. Methods. Open skeletal muscle biopsies were performed from the quadriceps muscle in four SMA1 patients and three age-matched controls. Standard techniques were used for immunohis- tochemistry of embryonic and foetal MyHCs. Type I, IIa and IIx MyHCs were assessed by applying quadruple immunofluorescence. Western blot was performed to analyse the amount of survival motor neuron (SMN) protein in the muscle samples.

Results. There were profound and early alterations in MyHC expression from 7 days of life com- pared to age-matched controls. The expression of type IIx MyHC was completely lost in SMA1 and instead developmental isoforms remained highly expressed. Foetal MyHC was still, at 3.5 months of age, expressed in the majority of muscle fibres in SMA1 patients, whereas it was completely downregulated in age-matched controls. The level of SMN protein was reduced in all SMN1 patients.

Conclusions. The abnormal pattern of MyHC expression in postnatal stages of SMA1 was ob- served early in the newborn period, which may have implications for the effects of gene therapy, since there are clear clinical benefits from early treatment. Whether such aberrant and delayed expression of MyHCs can be completely restored by postnatal gene therapy remains to be studied and may also have implications for new phenotypes that will evolve with new therapies.