Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells

Area of Science:

• Biochemistry
• Cell Biology
• Neuromuscular Diseases

Background:

• Maladaptive endoplasmic reticulum (ER) stress is linked to altered reactive oxygen species (ROS) production and mitochondrial dysfunction.
• These factors are implicated in the muscle weakness observed in myositis, an autoimmune neuromuscular disorder.

Purpose of the Study:

• To investigate the role of ROS generation in ER stress-induced mitochondrial dysfunction in skeletal muscle.
• To evaluate the therapeutic potential of the antioxidant Eukarion (EUK)-134 in mitigating these effects.

Main Methods:

• An in vitro model of ER stress was established in skeletal muscle cells using tunicamycin.
• Cells were treated with tunicamycin alone or in combination with EUK-134.
• Key markers of ER stress, mitochondrial function (membrane potential, respiration), mitochondrial dynamics (biogenesis, fusion, fission), and ROS generation were assessed.

Main Results:

• Tunicamycin induced maladaptive ER stress and significant mitochondrial dysfunction, including loss of membrane potential and impaired respiratory function.
• ER stress led to ROS-mediated mitochondrial biogenesis and fusion, paradoxically increasing fragmentation and upregulating fission markers.
• EUK-134 treatment ameliorated ER stress, improved mitochondrial function, and prevented increased cellular ROS generation, though mitochondrial superoxide levels remained unchanged.

Conclusions:

• Targeting ROS generation with EUK-134 can counteract ER stress-induced mitochondrial dysfunction and alterations in mitochondrial dynamics.
• Quenching ROS may represent a promising therapeutic strategy for muscle weakness and dysfunction associated with chronic ER stress conditions like myositis.