Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy.
Sci Rep
; 6: 28846, 2016 06 28.
Article
in En
| MEDLINE
| ID: mdl-27349908
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Muscular Atrophy, Spinal
/
Muscular Atrophy
/
Signal Transduction
/
Disease Models, Animal
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Sci Rep
Year:
2016
Document type:
Article
Country of publication:
United kingdom