title: Arsenic induces apoptosis in myoblasts through a reactive oxygen species-induced endoplasmic reticulum stress and mitochondrial dysfunction pathway.
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 (As(2)O(3)) on myoblasts. C2C12 myoblasts underwent apoptosis in response to As(2)O(3) (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, As(2)O(3) 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 As(2)O(3) (10 μM)-treated myoblasts. Furthermore, As(2)O(3) (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 As(2)O(3)-induced myoblast apoptosis. Taken together, these results suggest that As(2)O(3) may exert its cytotoxicity on myoblasts by inducing apoptosis through a ROS-induced mitochondrial dysfunction, ER stress, and Akt inactivation signaling pathway.
authors.affiliation: College of Medicine, Institute of Toxicology, National Taiwan University, Taipei, Taiwan.
authors.forename: Yuan-Peng
authors.initials: YP
authors.lastname: Yen
authors.forename: Keh-Sung
authors.initials: KS
authors.lastname: Tsai
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Chun-Fa
authors.initials: CF
authors.lastname: Huang
authors.forename: Rong-Sen
authors.initials: RS
authors.lastname: Yang
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000633:toxicity*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002460:Cell Line; D003603:Cytotoxins / Q000633:toxicity; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D032446:Myoblasts / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001152:Arsenicals; D003603:Cytotoxins; D010087:Oxides; D017382:Reactive Oxygen Species; D001151:Arsenic; D000077237:Arsenic Trioxide