Antioxidant Treatment and Induction of Autophagy Cooperate to Reduce Desmin Aggregation in a Cellular Model of Desminopathy.
Desminopathies, a subgroup of myofibrillar myopathies (MFMs), the progressive muscular diseases characterized by the accumulation of granulofilamentous desmin-positive aggregates, result from mutations in the desmin gene (DES), encoding a muscle-specific intermediate filament. Desminopathies often lead to severe disability and premature death from cardiac and/or respiratory failure; no specific treatment is currently available. To identify drug-targetable pathophysiological pathways, we performed pharmacological studies in C2C12 myoblastic cells expressing mutant DES. We found that inhibition of the Rac1 pathway (a G protein signaling pathway involved in diverse cellular processes), antioxidant treatment, and stimulation of macroautophagy reduced protein aggregation by up to 75% in this model. Further, a combination of two or three of these treatments was more effective than any of them alone. These results pave the way towards the development of the first treatments for desminopathies and are potentially applicable to other muscle or brain diseases associated with abnormal protein aggregation.
Physiopathology of the striated muscle laboratory, Unit of Functional and Adaptive Biology, University Paris Diderot, Sorbonne Paris Cité, UMR CNRS 8251, Paris, France.
Eva
E
Cabet
Physiopathology of the striated muscle laboratory, Unit of Functional and Adaptive Biology, University Paris Diderot, Sorbonne Paris Cité, UMR CNRS 8251, Paris, France.
Sabrina
S
Batonnet-Pichon
Physiopathology of the striated muscle laboratory, Unit of Functional and Adaptive Biology, University Paris Diderot, Sorbonne Paris Cité, UMR CNRS 8251, Paris, France.
Florence
F
Delort
Biology and pathology of the endocrine pancreas laboratory, Unit of Functional and Adaptive Biology, University Paris Diderot, Sorbonne Paris Cité, UMR CNRS 8251, Paris, France.
Blandine
B
Gausserès
Physiopathology of the striated muscle laboratory, Unit of Functional and Adaptive Biology, University Paris Diderot, Sorbonne Paris Cité, UMR CNRS 8251, Paris, France.
Patrick
P
Vicart
Physiopathology of the striated muscle laboratory, Unit of Functional and Adaptive Biology, University Paris Diderot, Sorbonne Paris Cité, UMR CNRS 8251, Paris, France.
Alain
A
Lilienbaum
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001343:Autophagy; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D003893:Desmin / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D009136:Muscular Dystrophies / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D024505:Tocopherols / Q000494:pharmacology
D000975:Antioxidants; D003893:Desmin; D024505:Tocopherols