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- Title
Arsenic induces apoptosis in myoblasts through a reactive oxygen species-induced endoplasmic reticulum stress and mitochondrial dysfunction pathway.
- Authors
Yen, Yuan-Peng; Tsai, Keh-Sung; Chen, Ya-Wen; Huang, Chun-Fa; Yang, Rong-Sen; Liu, Shing-Hwa
- Abstract
A pool of myoblasts available for myogenesis is important for skeletal muscle size. The decreased number of skeletal muscle fibers could be due to the decreased myoblast proliferation or cytotoxicity. Identification of toxicants that regulate myoblast apoptosis is important in skeletal muscle development or regeneration. Here, we investigate the cytotoxic effect and its possible mechanisms of arsenic trioxide (AsO) on myoblasts. C2C12 myoblasts underwent apoptosis in response to AsO (1-10 μM), accompanied by increased Bax/Bcl-2 ratio, decreased mitochondria membrane potential, increased cytochrome c release, increased caspase-3/-9 activity, and increased poly (ADP-ribose) polymerase (PARP) cleavage. Moreover, AsO triggered the endoplasmic reticulum (ER) stress indentified through several key molecules of the unfolded protein response, including glucose-regulated protein (GRP)-78, GRP-94, PERK, eIF2α, ATF6, and caspase-12. Pretreatment with antioxidant N-acetylcysteine (NAC, 0.5 mM) dramatically suppressed the increases in reactive oxygen species (ROS), lipid peroxidation, ER stress, caspase cascade activity, and apoptosis in AsO (10 μM)-treated myoblasts. Furthermore, AsO (10 μM) effectively decreased the phosphorylation of Akt, which could be reversed by NAC. Over-expression of constitutive activation of Akt (c.a. Akt) also significantly attenuated AsO-induced myoblast apoptosis. Taken together, these results suggest that AsO may exert its cytotoxicity on myoblasts by inducing apoptosis through a ROS-induced mitochondrial dysfunction, ER stress, and Akt inactivation signaling pathway.
- Subjects
PHYSIOLOGICAL effects of arsenic; APOPTOSIS; MYOBLASTS; SKELETAL muscle; ENDOPLASMIC reticulum; MYOGENESIS; ADENOSINE diphosphate ribose; REACTIVE oxygen species; PHYSIOLOGY
- Publication
Archives of Toxicology, 2012, Vol 86, Issue 6, p923
- ISSN
0340-5761
- Publication type
Article
- DOI
10.1007/s00204-012-0864-9