Faculty Opinions recommendation of Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy.

Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths.Previous studies have focused on deciphering disease pathogenesis in motor neurons.However, a systematic evaluation of atrophy pathways in muscles is lacking.Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice.Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn 2B/-mice but not in the more severe Smn -/-; SMN2 mice.Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn 2B/-muscle.Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy.Cardiac muscle also exhibits differential induction of atrophy between Smn 2B/-and Smn -/-; SMN2 mice, albeit in the opposite direction to that of skeletal muscle.Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity.We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels.Spinal muscular atrophy (SMA) is a childhood neuromuscular genetic disease affecting 1 in 6,000 to 10,000 live births 1,2 .SMA pathological hallmarks include motor neuron loss and severe muscle atrophy of the limb and trunk muscles.In 1995, the disease-causing gene, survival motor neuron 1 (SMN1), was identified 3 .A mutation or deletion in the SMN1 gene impairs SMN protein production.A second nearly identical copy of the gene, SMN2, is present at the same locus as SMN1 3 .However, a single base pair substitution in SMN2 profoundly limits its ability to produce full length SMN protein 4 .Thus, increasing SMN2 copy number leads to phenotypes of reduced severity that can be classified on a spectrum (reviewed in 5 ).The mouse only harbors a single Smn gene and homozygous loss is embryonically lethal 6 .The addition of a human SMN2 transgene to Smn -/-mice yielded the original mouse model of SMA (Smn -/-; SMN2; also referred to as the severe model), which presents with a severe phenotype and lives to a maximum of postnatal day (P) 6 7 .Recently, mouse models of SMA with less severe phenotypes have been generated in an effort to uncover novel disease mechanisms and to test several therapeutic approaches.One of these is the Smn 2B/-mouse model.Instead of incorporating the human SMN2 transgene, this mouse harbours a 3 nucleotide substitution in the exonic splice enhancer of exon 7 (2B mutation) in one allele of the mouse Smn gene, while the other allele is null 8,9 .Consequently, the mice present with a phenotype associated with a longer life span (~P30) and enhanced motor function relative to the Smn -/-; SMN2 mouse model 9 .It has always been assumed that muscle defects observed in SMA were completely attributable to degenerating motor neurons.However, recent work on both the Smn -/-; SMN2 and Smn 2B/-model mice revealed robust intrinsic muscle weakness prior to any overt motor neuron pathology 10 .Muscle weakness in these models was attributed to impaired muscle development supported by the aberrant expression of several proteins involved in myogenesis [10][11][12] .Atrophy, a direct consequence of motor neuron loss, is likely a contributing factor to muscle

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