Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies - potential role of ER stress pathways.
OBJECTIVE
Discussion of endoplasmic reticulum (ER) stress pathway activation in idiopathic inflammatory myopathies (IIM), and downstream mechanisms causative of muscle weakness.


RESULTS
In IIM, ER stress is an important pathogenic process, but how it causes muscle dysfunction is unknown. We discuss relevant pathways modified in response to ER stress in IIM: reactive oxygen species (ROS) generation and mitochondrial dysfunction, and muscle cytokine (myokine) generation. First, ER stress pathway activation can induce changes in mitochondrial bioenergetics and ROS production. ROS can oxidize cellular components, causing muscle contractile dysfunction and energy deficits. Novel compounds targeting ROS generation and/or mitochondrial dysfunction can improve muscle function in several myopathologies. Second, recent research has demonstrated that skeletal muscle produces multiple myokines. It is suggested that these play a role in causing muscle weakness. Myokines are capable of immune cell recruitment, thus contributing to perturbed muscle function. A characterization of myokines in IIM would clarify their pathogenic role, and so identify new therapeutic targets.


CONCLUSIONS
ER stress pathway activation is clearly of etiological relevance in IIM. Research to better understand mechanisms of weakness downstream of ER stress is now required, and which may discover new therapeutic targets for nonimmune cell-mediated weakness.
aMRC Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, UK bResearch Center for Genetic Medicine, Children's National Medical Center, Washington, D. C., United States of America cDepartment of Integrative Systems Biology, George Washington University School of Medicine, Washington, D. C., United States of America.
Adam P
AP
Lightfoot
Kanneboyina
K
Nagaraju
Anne
A
McArdle
Robert G
RG
Cooper
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000503:physiopathology*; D018908:Muscle Weakness / Q000378:metabolism / Q000503:physiopathology*; D009220:Myositis / Q000378:metabolism / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D016207:Cytokines; D017382:Reactive Oxygen Species