Altered in vitro proliferation of mouse SOD1-G93A skeletal muscle satellite cells.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neurodegenerative disease characterized by ascending muscle weakness, atrophy and paralysis. Early muscle abnormalities that precede motor neuron loss in ALS may destabilize neuromuscular junctions, and we have previously demonstrated alterations in myogenic regulatory factor (MRF) expression in vivo and in the activation of myofiber-associated skeletal muscle satellite cells (SMSCs) in the mouse model of ALS (SOD1-G93A).


METHODS
To elucidate niche dependence versus cell-autonomous mutant SOD1 (mSOD1) toxicity in this model, we measured in vitro proliferation potential and MRF and cyclin gene expression in SMSC cultures derived from fast-twitch extensor digitorum longus and slow-twitch soleus muscles of SOD1-G93A mice.


RESULTS
SMSCs from early presymptomatic (p40) to terminal, semi-paralytic (p120) SOD1-G93A mice demonstrated generally lower proliferation potential compared with age-matched controls. However, induced proliferation was observed in surgically denervated wild-type animals and SOD1-G93A animals at p90, when critical denervation arises. SMSCs from fast and slow muscles were similarly affected by mSOD1 expression. Lowered proliferation rate was generally corroborated with decreased relative MRF expression levels, although this was most prominent in early age and was modulated by muscle type origin. Cyclins controlling cell proliferation did not show modifications in their mRNA levels; however, the expression of cyclin-dependent kinase inhibitor 1A (Cdkn1a), which is known to promote myoblast differentiation, was decreased in SOD1-G93A cultures.


CONCLUSIONS
Our data suggest that the function of SMSCs is impaired in SOD1-G93A satellite cells from the earliest stages of the disease when no critical motor neuron loss has been described.
LAGENBIO-I3A, Aragon's Institute of Health Sciences, University of Zaragoza, Zaragoza, Spain.
Raquel
R
Manzano
Janne M
JM
Toivonen
Ana C
AC
Calvo
Sara
S
Oliván
Pilar
P
Zaragoza
Clementina
C
Rodellar
Didier
D
Montarras
Rosario
R
Osta
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032496:Satellite Cells, Skeletal Muscle / Q000201:enzymology* / Q000473:pathology*; D013482:Superoxide Dismutase / Q000502:physiology*
C109415:SOD1 G93A protein; D013482:Superoxide Dismutase