Antioxidant Treatment and Induction of Autophagy Cooperate to Reduce Desmin Aggregation in a Cellular Model of Desminopathy

PloS One
Eva CabetAlain Lilienbaum

Abstract

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.

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Citations

Dec 29, 2016·Antioxidants & Redox Signaling·Emmeran Le MoalRémi Mounier
Mar 9, 2017·Journal of Neuromuscular Diseases·Sabrina Batonnet-PichonAlain Lilienbaum
Dec 1, 2017·Cell Stress & Chaperones·Ivan DimauroDaniela Caporossi
Aug 28, 2016·Journal of Cell Science·Antigoni DiokmetzidouYassemi Capetanaki
Jun 22, 2018·Biophysics Reviews·Andreas BrodehlHendrik Milting
Sep 8, 2020·Journal of Cachexia, Sarcopenia and Muscle·Henning T LangerKeith Baar
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Nov 7, 2017·Analytical Cellular Pathology (Amsterdam)·Lihua FanXiaoyan Yu
Jul 28, 2020·Redox Biology·Álvaro Viedma-PoyatosDolores Pérez-Sala
Aug 2, 2019·Experimental Cell Research·Florence DelortSabrina Batonnet-Pichon
May 1, 2021·International Journal of Molecular Sciences·Lorenzo MaggiGiovanna Lattanzi
Feb 28, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Natalia SmolinaAnna Kostareva

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Methods Mentioned

BETA
transfection
GTPase
flow cytometry
transfections
confocal microscopy
protein kinase C

Software Mentioned

R
ImageJ

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