We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Arsenic Stimulates Myoblast Mitochondrial Epidermal Growth Factor Receptor to Impair Myogenesis.
- Authors
Cheikhi, Amin; Anguiano, Teresa; Lasak, Jane; Qian, Baoli; Sahu, Amrita; Mimiya, Hikaru; Cohen, Charles C; Wipf, Peter; Ambrosio, Fabrisia; Barchowsky, Aaron
- Abstract
Arsenic exposure impairs muscle metabolism, maintenance, progenitor cell differentiation, and regeneration following acute injury. Low to moderate arsenic exposures target muscle fiber and progenitor cell mitochondria to epigenetically decrease muscle quality and regeneration. However, the mechanisms for how low levels of arsenic signal for prolonged mitochondrial dysfunction are not known. In this study, arsenic attenuated murine C2C12 myoblasts differentiation and resulted in abnormal undifferentiated myoblast proliferation. Arsenic prolonged ligand-independent phosphorylation of mitochondrially localized epidermal growth factor receptor (EGFR), a major driver of proliferation. Treating cells with a selective EGFR kinase inhibitor, AG-1478, prevented arsenic inhibition of myoblast differentiation. AG-1478 decreased arsenic-induced colocalization of pY845EGFR with mitochondrial cytochrome C oxidase subunit II, as well as arsenic-enhanced mitochondrial membrane potential, reactive oxygen species generation, and cell cycling. All of the arsenic effects on mitochondrial signaling and cell fate were mitigated or reversed by addition of mitochondrially targeted agents that restored mitochondrial integrity and function. Thus, arsenic-driven pathogenesis in skeletal muscle requires sustained mitochondrial EGFR activation that promotes progenitor cell cycling and proliferation at the detriment of proper differentiation. Collectively, these findings suggest that the arsenic-activated mitochondrial EGFR pathway drives pathogenic signaling for impaired myoblast metabolism and function.
- Subjects
MYOBLASTS; EPIDERMAL growth factor receptors; CYTOCHROME oxidase; REACTIVE oxygen species; ARSENIC; MYOGENESIS; MUSCLE regeneration
- Publication
Toxicological Sciences, 2020, Vol 176, Issue 1, p162
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfaa031