Abstract
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 Smn2B/− 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 Smn2B/− muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn2B/− 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.
Highlights
Weakness, but it has not been systematically studied in Spinal muscular atrophy (SMA)
The MyoG pathway becomes activated only in neurogenic atrophy[15,16]. This pathway has been previously investigated in the SmnΔ7 model mice (Smn−/−; SMN2+/+; SmnΔ7+/+) and SMA patients where increased myogenin expression correlated with increased expression of Muscle Ring Finger 1 (MuRF1, TRIM63) and Atrogin-1 (MAFbx, Fbxo32) in skeletal muscles[17]
Atrophy in skeletal muscles from Smn−/−; SMN2 mice is marked by increased proteasomal degradation without signs of autophagosomal protein breakdown
Summary
Weakness, but it has not been systematically studied in SMA. Different atrophy initiating stimuli, such as fasting, denervation, and other systemic catabolic states activate common transcriptional changes in the atrogenes[13,14]. The MyoG pathway becomes activated only in neurogenic atrophy[15,16] This pathway has been previously investigated in the SmnΔ7 model mice (Smn−/−; SMN2+/+; SmnΔ7+/+) and SMA patients where increased myogenin expression correlated with increased expression of Muscle Ring Finger 1 (MuRF1, TRIM63) and Atrogin-1 (MAFbx, Fbxo32) in skeletal muscles[17]. FoxO proteins induce the expression of proteasomal genes, such as MuRF1 and Atrogin-1, as well as autophagic genes[21,22,23] This dual pathway control is important since autophagy has been reported to contribute to atrophy upon denervation[21,22,23]. We extended our analysis to cardiac muscle, which has been previously described to have smaller caliber fibers[24]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
