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Time-Point Dependent Activation of Autophagy and the UPS in SOD1G93A Mice Skeletal Muscle.

Oliván S, Calvo AC, Gasco S, Muñoz MJ, Zaragoza P, Osta R - PLoS ONE (2015)

Bottom Line: In particular, the two main intracellular degradation mechanisms, autophagy and the ubiquitin-proteasome degradative system (UPS) have been poorly studied in this tissue.Our results showed a significant upregulation of proteasome activity at early symptomatic stage, while the autophagy activation was found at presymptomatic and terminal stages.The mRNA upregulated levels of LC3, p62, Beclin1, Atg5 and E2f1 were only observed at symptomatic and terminal stages, which reinforced the time-point activation of autophagy.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética y Bioquímica (LAGENBIO), Facultad de Veterinaria, Instituto Agroalimentario de Aragón (IA2), Instituto de Investigación Sanitaria Aragón, Universidad de Zaragoza, Zaragoza, Spain.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by a selective loss of motor neurons together with a progressive muscle weakness. Albeit the pathophysiological mechanisms of the disease remain unknown, growing evidence suggests that skeletal muscle can be a target of ALS toxicity. In particular, the two main intracellular degradation mechanisms, autophagy and the ubiquitin-proteasome degradative system (UPS) have been poorly studied in this tissue. In this study we investigated the activation of autophagy and the UPS as well as apoptosis in the skeletal muscle from SOD1G93A mice along disease progression. Our results showed a significant upregulation of proteasome activity at early symptomatic stage, while the autophagy activation was found at presymptomatic and terminal stages. The mRNA upregulated levels of LC3, p62, Beclin1, Atg5 and E2f1 were only observed at symptomatic and terminal stages, which reinforced the time-point activation of autophagy. Furthermore, no apoptosis activation was observed along disease progression. The combined data provided clear evidence for the first time that there is a time-point dependent activation of autophagy and UPS in the skeletal muscle from SOD1G93A mice.

No MeSH data available.


Related in: MedlinePlus

mRNA expression levels of autophagy markers.Relative expression values of Lc3, p62, Beclin1, Atg5 and E2f1 in SOD1G93A mice (grey bars) and wild type mice (WT, black bars) at each studied stage. Each data point represented the mean ± SEM. n = 10 animals per time-point and genotype. *p <0.05, **p <0.01 and ***p <0.001 versus age-matched WT.
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pone.0134830.g001: mRNA expression levels of autophagy markers.Relative expression values of Lc3, p62, Beclin1, Atg5 and E2f1 in SOD1G93A mice (grey bars) and wild type mice (WT, black bars) at each studied stage. Each data point represented the mean ± SEM. n = 10 animals per time-point and genotype. *p <0.05, **p <0.01 and ***p <0.001 versus age-matched WT.

Mentions: To characterize the autophagy machinery in SOD1G93A mice along disease progression, the mRNA levels of Lc3, p62, Beclin1, Atg5 and E2f1 genes were first quantified by real-time PCR in the skeletal muscle tissue of WT and SOD1G93A mice at P40, P60, P90 and P120. At asymptomatic stage (P40) no significant changes were found. At early symptomatic stage (P60), mRNA levels of Beclin1 and Atg5 were significantly downregulated in SOD1G93A mice, while upregulated levels were found in the case of E2f1. However, at symptomatic and terminal stages of the disease (P90 and P120) all the analyzed transcripts were significantly upregulated (Fig 1).


Time-Point Dependent Activation of Autophagy and the UPS in SOD1G93A Mice Skeletal Muscle.

Oliván S, Calvo AC, Gasco S, Muñoz MJ, Zaragoza P, Osta R - PLoS ONE (2015)

mRNA expression levels of autophagy markers.Relative expression values of Lc3, p62, Beclin1, Atg5 and E2f1 in SOD1G93A mice (grey bars) and wild type mice (WT, black bars) at each studied stage. Each data point represented the mean ± SEM. n = 10 animals per time-point and genotype. *p <0.05, **p <0.01 and ***p <0.001 versus age-matched WT.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526523&req=5

pone.0134830.g001: mRNA expression levels of autophagy markers.Relative expression values of Lc3, p62, Beclin1, Atg5 and E2f1 in SOD1G93A mice (grey bars) and wild type mice (WT, black bars) at each studied stage. Each data point represented the mean ± SEM. n = 10 animals per time-point and genotype. *p <0.05, **p <0.01 and ***p <0.001 versus age-matched WT.
Mentions: To characterize the autophagy machinery in SOD1G93A mice along disease progression, the mRNA levels of Lc3, p62, Beclin1, Atg5 and E2f1 genes were first quantified by real-time PCR in the skeletal muscle tissue of WT and SOD1G93A mice at P40, P60, P90 and P120. At asymptomatic stage (P40) no significant changes were found. At early symptomatic stage (P60), mRNA levels of Beclin1 and Atg5 were significantly downregulated in SOD1G93A mice, while upregulated levels were found in the case of E2f1. However, at symptomatic and terminal stages of the disease (P90 and P120) all the analyzed transcripts were significantly upregulated (Fig 1).

Bottom Line: In particular, the two main intracellular degradation mechanisms, autophagy and the ubiquitin-proteasome degradative system (UPS) have been poorly studied in this tissue.Our results showed a significant upregulation of proteasome activity at early symptomatic stage, while the autophagy activation was found at presymptomatic and terminal stages.The mRNA upregulated levels of LC3, p62, Beclin1, Atg5 and E2f1 were only observed at symptomatic and terminal stages, which reinforced the time-point activation of autophagy.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Genética y Bioquímica (LAGENBIO), Facultad de Veterinaria, Instituto Agroalimentario de Aragón (IA2), Instituto de Investigación Sanitaria Aragón, Universidad de Zaragoza, Zaragoza, Spain.

ABSTRACT
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by a selective loss of motor neurons together with a progressive muscle weakness. Albeit the pathophysiological mechanisms of the disease remain unknown, growing evidence suggests that skeletal muscle can be a target of ALS toxicity. In particular, the two main intracellular degradation mechanisms, autophagy and the ubiquitin-proteasome degradative system (UPS) have been poorly studied in this tissue. In this study we investigated the activation of autophagy and the UPS as well as apoptosis in the skeletal muscle from SOD1G93A mice along disease progression. Our results showed a significant upregulation of proteasome activity at early symptomatic stage, while the autophagy activation was found at presymptomatic and terminal stages. The mRNA upregulated levels of LC3, p62, Beclin1, Atg5 and E2f1 were only observed at symptomatic and terminal stages, which reinforced the time-point activation of autophagy. Furthermore, no apoptosis activation was observed along disease progression. The combined data provided clear evidence for the first time that there is a time-point dependent activation of autophagy and UPS in the skeletal muscle from SOD1G93A mice.

No MeSH data available.


Related in: MedlinePlus