Suppressed autophagy flux in skeletal muscle of an amyotrophic lateral sclerosis mouse model during disease progression

Accumulation of abnormal protein inclusions is implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Autophagy, an intracellular process targeting misfolded proteins and damaged organelles for lysosomal degradation, plays crucial roles in survival and diseased conditions. E...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Physiological reports 2015-01, Vol.3 (1), p.e12271-n/a
Hauptverfasser: Xiao, Yajuan, Ma, Changling, Yi, Jianxun, Wu, Shaoping, Luo, Guo, Xu, Xiulong, Lin, Pei‐Hui, Sun, Jun, Zhou, Jingsong
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Accumulation of abnormal protein inclusions is implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Autophagy, an intracellular process targeting misfolded proteins and damaged organelles for lysosomal degradation, plays crucial roles in survival and diseased conditions. Efforts were made to understand the role of autophagy in motor neuron degeneration and to target autophagy in motor neuron for ALS treatment. However, results were quite contradictory. Possible autophagy defects in other cell types may also complicate the results. Here, we examined autophagy activity in skeletal muscle of an ALS mouse model G93A. Through overexpression of a fluorescent protein LC3‐RFP, we found a basal increase in autophagosome formation in G93A muscle during disease progression when the mice were on a regular diet. As expected, an autophagy induction procedure (starvation plus colchicine) enhanced autophagy flux in skeletal muscle of normal mice. However, in response to the same autophagy induction procedure, G93A muscle showed significant reduction in the autophagy flux. Immunoblot analysis revealed that increased cleaved caspase‐3 associated with apoptosis was linked to the cleavage of several key proteins involved in autophagy, including Beclin‐1, which is an essential molecule connecting autophagy and apoptosis pathways. Taking together, we provide the evidence that the cytoprotective autophagy pathway is suppressed in G93A skeletal muscle and this suppression may link to the enhanced apoptosis during ALS progression. The abnormal autophagy activity in skeletal muscle likely contributes muscle degeneration and disease progression in ALS. e12271 Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disease, in which skeletal muscle is substantially affected. This study discovered a specific defect in autophagy pathway in skeletal muscle, which likely plays an important role in ALS disease progression.
ISSN:2051-817X
2051-817X
DOI:10.14814/phy2.12271