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

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.

Systemic overexpression of SQSTM1/p62 accelerates disease onset in a SOD1H46R-expressing ALS mouse model

“…Second possibility is that SQSTM1 expressing in cells and tissues other than neurons affects the onset of disease in SOD1 H46R mice. Evidences showing that, in skeletal muscle of a SOD1 G93A -expressing ALS mouse model, the UPS is activated prior to the onset of disease, while the autophagic degradation pathway is activated after the onset of disease till at end-stage [ 36 ], suggest a possible pathogenic interaction between proteostasis in skeletal muscles and neurodegeneration. Since the expression level of transgene-coded SQSTM1 in skeletal muscle is higher than those in other tissues (Additional file 1 : Figure S1b), it is possible that the earlier onset of disease in SQSTM1 ; SOD1 H46R mice is linked to dysregulation of autophagy by SQSTM1 overexpression in skeletal muscles.…”

Oxidative stress induces dysregulated autophagy in corneal epithelium of keratoconus patients

“…In addition, we found LC3-II and LAMP-1 were significantly decreased in the cone region of KC epithelium from Grades II and III compared to the peripheral region. This could be due to insufficient autophagy activity in the diseased area (cone) compared to the matched peripheral region during disease progression or an altered expression of autophagic markers, which has been observed in other disease conditions [ 28 , 29 ]. A difference in the expression levels (low, medium, high) of autophagosomal marker LC3 has been shown in KC epithelium, but without clinical disease classification, thereby demonstrating alterations in the autophagic pathway [ 30 ].…”

Expression profile of pattern recognition receptors in skeletal muscle of SOD1(G93A) amyotrophic lateral sclerosis (ALS) mice and sporadic ALS patients

“…In this context, it was shown that skeletal muscle‐restricted expression of mutant human SOD1 (hSOD1) causes motor neuron degeneration in an ALS mouse model , and recent findings suggest that skeletal muscle may actively participate in ALS pathogenesis. Indeed, gene expression changes, increased oxidative stress, impaired protein degradation, defective mitochondrial dynamics and disturbed calcium homeostasis in the skeletal muscle from ALS animal models and human ALS patients were detected early in disease progression . Furthermore, activation of inflammatory pathways in the context of tissue remodelling have been described in skeletal muscle of SOD1 (G93A) rats and in human sALS patients .…”