Redox Signaling and Stress in Inherited Myopathies

Significance: Reactive oxygen species (ROS) are highly reactive compounds that behave like a double-edged sword; they damage cellular structures and act as second messengers in signal transduction. Mitochondria and endoplasmic reticulum (ER) are interconnected organelles with a central role in ROS production, detoxification, and oxidative stress response. Skeletal muscle is the most abundant tissue in mammals and one of the most metabolically active ones and thus relies mainly on oxidative phosphorylation (OxPhos) to synthesize adenosine triphosphate. The impairment of OxPhos leads to myopathy and increased ROS production, thus affecting both redox poise and signaling. In addition, ROS enter the ER and trigger ER stress and its maladaptive response, which also lead to a myopathic phenotype with mitochondrial involvement. Here, we review the role of ROS signaling in myopathies due to either mitochondrial or ER dysfunction. Recent Advances: Relevant advances have been evolving over the last 10 years on the intricate ROS-dependent pathways that act as modifiers of the disease course in several myopathies. To this end, pathways related to mitochondrial biogenesis, satellite cell differentiation, and ER stress have been studied extensively in myopathies. Critical Issues: The analysis of the chemistry and the exact quantitation, as well as the localization of ROS, are still challenging due to the intrinsic labile nature of ROS and the technical limitations of their sensors. Future Directions: The mechanistic studies of the pathogenesis of mitochondrial and ER-related myopathies offer a unique possibility to discover novel ROS-dependent pathways. Antioxid. Redox Signal. 37, 301–323.