Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy.
BACKGROUND
Spinal muscular atrophy (SMA) is a neurodegenerative disorder associated with mutations of the survival motor neuron gene SMN and is characterized by muscle weakness and atrophy caused by degeneration of spinal motor neurons. SMN has a role in neurons but its deficiency may have a direct effect on muscle tissue.


METHODS
We applied microarray and quantitative real-time PCR to study at transcriptional level the effects of a defective SMN gene in skeletal muscles affected by the two forms of SMA: the most severe type I and the mild type III.


RESULTS
The two forms of SMA generated distinct expression signatures: the SMA III muscle transcriptome is close to that found under normal conditions, whereas in SMA I there is strong alteration of gene expression. Genes implicated in signal transduction were up-regulated in SMA III whereas those of energy metabolism and muscle contraction were consistently down-regulated in SMA I. The expression pattern of gene networks involved in atrophy signaling was completed by qRT-PCR, showing that specific pathways are involved, namely IGF/PI3K/Akt, TNF-alpha/p38 MAPK and Ras/ERK pathways.


CONCLUSIONS
Our study suggests a different picture of atrophy pathways in each of the two forms of SMA. In particular, p38 may be the regulator of protein synthesis in SMA I. The SMA III profile appears as the result of the concurrent presence of atrophic and hypertrophic fibers. This more favorable condition might be due to the over-expression of MTOR that, given its role in the activation of protein synthesis, could lead to compensatory hypertrophy in SMA III muscle fibers.
CRIBI Biotechnology Centre, University of Padova, Padova, Italy. caterina@cribi.unipd.it
Caterina
C
Millino
Marina
M
Fanin
Andrea
A
Vettori
Paolo
P
Laveder
Maria Luisa
ML
Mostacciuolo
Corrado
C
Angelini
Gerolamo
G
Lanfranchi
D017209:Apoptosis; D001706:Biopsy; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000145:classification / Q000235:genetics* / Q000473:pathology; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D055532:SMN Complex Proteins / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008565:Membrane Proteins; C496800:NAIP protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C087360:RRAS2 protein, human; D020559:Monomeric GTP-Binding Proteins