Skeletal Muscle Is a Primary Target of SOD1G93A-Mediated Toxicity

Dobrowolny, Gabriella; Aucello, Michela; Rizzuto, Emanuele; Beccafico, Sara; Mammucari, Cristina; Boncompagni, Simona; Belia, Silvia; Wannenes, Francesca; Nicoletti, Carmine; Prete, Zaccaria Del; Rosenthal, Nadia; Molinaro, Mario; Protasi, Feliciano; Fanò, Giorgio; Sandri, Monica; Musarò, Antonio

doi:10.1016/j.cmet.2008.12.003

Cited by 41 publications

(80 citation statements)

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“…These changes in gene expression appear to be coordinated in the direction of a fast-to-slow transformation [36]. Consistently, the expression profiles of denervated muscles revealed the molecular signature of a reduced metabolic activity [37].…”

Section: Discussionmentioning

confidence: 53%

Mitochondrial Network Genes in the Skeletal Muscle of Amyotrophic Lateral Sclerosis Patients

et al. 2013

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Recent evidence suggested that muscle degeneration might lead and/or contribute to neurodegeneration, thus it possibly play a key role in the etiopathogenesis and progression of amyotrophic lateral sclerosis (ALS). To test this hypothesis, this study attempted to categorize functionally relevant genes within the genome-wide expression profile of human ALS skeletal muscle, using microarray technology and gene regulatory network analysis. The correlation network structures significantly change between patients and controls, indicating an increased inter-gene connection in patients compared to controls. The gene network observed in the ALS group seems to reflect the perturbation of muscle homeostasis and metabolic balance occurring in affected individuals. In particular, the network observed in the ALS muscles includes genes (PRKR1A, FOXO1, TRIM32, ACTN3, among others), whose functions connect the sarcomere integrity to mitochondrial oxidative metabolism. Overall, the analytical approach used in this study offer the possibility to observe higher levels of correlation (i.e. common expression trends) among genes, whose function seems to be aberrantly activated during the progression of muscle atrophy.

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Section: Discussionmentioning

confidence: 53%

Mitochondrial Network Genes in the Skeletal Muscle of Amyotrophic Lateral Sclerosis Patients

et al. 2013

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“…We also show that the autophagy-related genes Gabarapl1, Ambra1, Uvrag and PARKIN expressions are augmented in the LPS + CMV group compared with the LPS group. However, severe oxidative stress and abnormalities in mitochondrial fission/fusion can trigger excessive autophagy and atrophy of skeletal muscles (48,49). But, its suppression may also lead to more muscle weakness as recently reported in ICU patients in whom early parenteral nutrition-induced suppression of autophagy explained its adverse effect on muscle weakness (47).…”

Section: Increased Autophagymentioning

confidence: 94%

Effects of Controlled Mechanical Ventilation on Sepsis-Induced Diaphragm Dysfunction in Rats

Maes¹,

Stamiris²,

Thomas³

et al. 2014

Critical Care Medicine

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“…Several studies have thus been carried out to understand whether mutSOD1 toxicity is confined to motoneurons, or whether the other cell types are also directly affected, thus playing a direct role in the disease. IGF-1 (insulin-like growth factor-1), can increase survival of tg ALS mice [45,[48][49][50] acting as trophic factors capable of enhancing survival of spinal cord motoneurons [51,52]. Interestingly, dysfunction of skeletal muscles and degeneration of neuromuscular junctions precede disease onset and motoneuron loss in tg ALS mice [42,43].…”

Section: Other Cellular Targets Of Misfolded Protein Toxicitymentioning

confidence: 99%

Motoneuronal and muscle-selective removal of ALS-related misfolded proteins

Crippa

Galbiati

Boncoraglio

et al. 2013

Biochemical Society Transactions

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ALS (amyotrophic lateral sclerosis), a fatal motoneuron (motor neuron) disease, occurs in clinically indistinguishable sporadic (sALS) or familial (fALS) forms. Most fALS-related mutant proteins identified so far are prone to misfolding, and must be degraded in order to protect motoneurons from their toxicity. This process, mediated by molecular chaperones, requires proteasome or autophagic systems. Motoneurons are particularly sensitive to misfolded protein toxicity, but other cell types such as the muscle cells could also be affected. Muscle-restricted expression of the fALS protein mutSOD1 (mutant superoxide dismutase 1) induces muscle atrophy and motoneuron death. We found that several genes have an altered expression in muscles of transgenic ALS mice at different stages of disease. MyoD, myogenin, atrogin-1, TGFβ1 (transforming growth factor β1) and components of the cell response to proteotoxicity [HSPB8 (heat shock 22kDa protein 8), Bag3 (Bcl-2-associated athanogene 3) and p62] are all up-regulated by mutSOD1 in skeletal muscle. When we compared the potential mutSOD1 toxicity in motoneuron (NSC34) and muscle (C2C12) cells, we found that muscle ALS models possess much higher chymotryptic proteasome activity and autophagy power than motoneuron ALS models. As a result, mutSOD1 molecular behaviour was found to be very different. MutSOD1 clearance was found to be much higher in muscle than in motoneurons. MutSOD1 aggregated and impaired proteasomes only in motoneurons, which were particularly sensitive to superoxide-induced oxidative stress. Moreover, in muscle cells, mutSOD1 was found to be soluble even after proteasome inhibition. This effect could be associated with a higher mutSOD1 autophagic clearance. Therefore muscle cells seem to manage misfolded mutSOD1 more efficiently than motoneurons, thus mutSOD1 toxicity in muscle may not directly depend on aggregation.

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Skeletal Muscle Is a Primary Target of SOD1G93A-Mediated Toxicity

Cited by 41 publications

References 0 publications

Mitochondrial Network Genes in the Skeletal Muscle of Amyotrophic Lateral Sclerosis Patients

Mitochondrial Network Genes in the Skeletal Muscle of Amyotrophic Lateral Sclerosis Patients

Effects of Controlled Mechanical Ventilation on Sepsis-Induced Diaphragm Dysfunction in Rats

Motoneuronal and muscle-selective removal of ALS-related misfolded proteins

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