A maladaptive ER stress response triggers dysfunction in highly active muscles of mice with SELENON loss

Abstract

Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to human SELENON-related myopathies. SelenoN knockout (KO) mouse limb muscles, however, are protected from the disease, and display no major alterations in muscle histology or contractile properties. Interestingly, we find that the highly active diaphragm muscle shows impaired force production, in line with the human phenotype. In addition, after repeated stimulation with a protocol which induces muscle fatigue, also hind limb muscles show altered relaxation times. Mechanistically, muscle SELENON loss alters activity-dependent calcium handling selectively impinging on the Ca2+ uptake of the sarcoplasmic reticulum and elicits an ER stress response, including the expression of the maladaptive CHOP-induced ERO1. In SELENON-devoid models, ERO1 shifts ER redox to a more oxidised poise, and further affects Ca2+ uptake. Importantly, CHOP ablation in SelenoN KO mice completely prevents diaphragm dysfunction, the prolonged limb muscle relaxation after fatigue, and restores Ca2+ uptake by attenuating the induction of ERO1. These findings suggest that SELENON is part of an ER stress-dependent antioxidant response and that the CHOP/ERO1 branch of the ER stress response is a novel pathogenic mechanism underlying SELENON-related myopathies.

Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity

“…S4). This suggests an important role of SEPN1 during ER stress response, as has been hypothesized (23,24).…”

SR stress in locomotor muscles of patients with chronic obstructive pulmonary disease

“…The coupling between calcium regulation and protein folding functions of muscle SR has been proposed recently (33). Accordingly, we hypothesized that the COPD participants will show reduced SERCA activity than control group.…”

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

“…Oxidation of Cys875 and/or Cys887 has been linked to the negative regulation of SERCA2 activity. Knockdown or knockout of SEPN1 or ERdj5 (both implicated in SERCA2 Cys875/887 reduction) correlates with decreased SERCA2 activity and lower [Ca 2+ ] ER [ 136 , 138 , 139 , 140 ]. Overexpression of a mammalian SERCA2 with mutated cysteine residues 875 and 887 (reasoned to behave like a reduced SERCA2) in Xenopus oocytes increased Ca 2+ oscillation frequency relative to that observed with wild-type SERCA2, suggesting an increase in SERCA2 pumping [ 141 ].…”