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Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells
Nye, Gareth Thoma, Anastasia Lyon, Max Al-Shanti, Nasser Cooper, Robert Lightfoot, Adam
Nye, Gareth
Thoma, Anastasia
Lyon, Max
Al-Shanti, Nasser
Cooper, Robert
Lightfoot, Adam
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Abstract
Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen
species (ROS) generation and mitochondrial abnormalities; and is postulated as a potential mechanism
involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study
investigates the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using
the ER stress inducer tunicamycin (24 h) in the presence or absence of a superoxide dismutase/catalase
mimetic Eukarion (EUK)-134. Tunicamycin induced maladaptive ER stress, which was mitigated by
EUK-134 at the transcriptional level. ER stress promoted mitochondrial dysfunction, described by
substantial loss of mitochondrial membrane potential, as well as a reduction in respiratory control
ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated
by EUK-134. Tunicamycin induced ROS-mediated biogenesis and fusion of mitochondria, which,
however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of
fission-related markers. Increased cellular ROS generation was observed under ER stress that was
prevented by EUK-134, even though no changes in mitochondrial superoxide were noticeable. These
findings suggest that targeting ROS generation using EUK-134 can amend aspects of ER stress-induced
changes in mitochondrial dynamics and function, and therefore, in instances of chronic ER stress,
such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness
and dysfunction.
Citation
Thoma, A., Lyon, M., Al-Shanti, N., Nye, G.A., Cooper, R.G., Lightfoot, A.P. (2020) Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells. Antioxidants, 9, 710.
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MDPI
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Antioxidants
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Article
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2076-3921