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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

Proteasome activity.Proteasome activity was measured in skeletal muscle homogenates from SOD1G93A mice (grey bars) and age-matched wild type mice (WT, black bars) at each stage of the disease. Data showed mean ± SEM. n = 6 animals per time-point and genotype. *p <0.05 and ***p <0.001.
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pone.0134830.g004: Proteasome activity.Proteasome activity was measured in skeletal muscle homogenates from SOD1G93A mice (grey bars) and age-matched wild type mice (WT, black bars) at each stage of the disease. Data showed mean ± SEM. n = 6 animals per time-point and genotype. *p <0.05 and ***p <0.001.

Mentions: Proteasome activation is the primary pathway by which proteins are cleared from cells [25]. Given the late activation of autophagy in SOD1G93A mice, we further investigated whether autophagy impairment influenced proteasomal activation at early stages. For these purpose, we measured the activity of the 20S proteolytic component of the 26S proteasome. In SOD1G93A mice, the proteasomal activity was significantly reduced at P40, P90 and P120, while at P60 the proteasome was significantly activated (Fig 4). These results suggested an impairment in proteasome function in the skeletal muscle of SOD1G93A mice in the main stages of the disease and the activation peak at P60 could imply a time-dependent way of action in the proteasomal degradation.


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)

Proteasome activity.Proteasome activity was measured in skeletal muscle homogenates from SOD1G93A mice (grey bars) and age-matched wild type mice (WT, black bars) at each stage of the disease. Data showed mean ± SEM. n = 6 animals per time-point and genotype. *p <0.05 and ***p <0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134830.g004: Proteasome activity.Proteasome activity was measured in skeletal muscle homogenates from SOD1G93A mice (grey bars) and age-matched wild type mice (WT, black bars) at each stage of the disease. Data showed mean ± SEM. n = 6 animals per time-point and genotype. *p <0.05 and ***p <0.001.
Mentions: Proteasome activation is the primary pathway by which proteins are cleared from cells [25]. Given the late activation of autophagy in SOD1G93A mice, we further investigated whether autophagy impairment influenced proteasomal activation at early stages. For these purpose, we measured the activity of the 20S proteolytic component of the 26S proteasome. In SOD1G93A mice, the proteasomal activity was significantly reduced at P40, P90 and P120, while at P60 the proteasome was significantly activated (Fig 4). These results suggested an impairment in proteasome function in the skeletal muscle of SOD1G93A mice in the main stages of the disease and the activation peak at P60 could imply a time-dependent way of action in the proteasomal degradation.

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