Unravelling the Role of Ascorbic Acid and ER Stress in SEPN1-Related Myopathy

Pozzer, Diego (2020). Unravelling the Role of Ascorbic Acid and ER Stress in SEPN1-Related Myopathy. PhD thesis The Open University.

Abstract

Selenoprotein N1 (SEPN1) is a member of the selenocysteine-containing protein family, that is localised in the endoplasmic reticulum (ER) and ubiquitously expressed throughout the body.

Mutations in the human SEPN1 gene were identified as the genetic cause of a muscle disease referred as SEPN1-related myopathy (SEPN1-RM), in which the main clinical features are axial weakness, scoliosis, a variable degree of spinal rigidity, respiratory failure and insulin resistance.

The selective muscle phenotype of the human SEPN1 loss of function, the redox nature of SEPN1, and the fact that SEPN1-depleted cells show oxidative stress support the idea that SEPN1 may be involved in protecting muscle ER redox homeostasis.

Ascorbic acid is an important antioxidant that is localized in the cytoplasm and in the endoplasmic reticulum lumen, since it is a cofactor needed in the folding of pro-collagen. Malnutrition characterized by low intake of ascorbic acid affects skeletal muscles, in terms of fatigue and myalgia.

Thus, both ascorbic acid and SEPN1 deficiency bring to the development of a myopathic condition, which can be explained by the fact that the two molecules have overlapping functions and intracellular localization.

To test the hypothesis that the anti-oxidant vitamin ascorbic acid protects SEPN1 knock out (KO) muscles from the consequences of SEPN1 loss of function we developed a mouse model mutant of SEPN1, which is also dependent on exogenous ascorbic acid. Our findings showed that a limited intake of ascorbic acid triggers ER stress and exacerbates SEPN1-related myopathic phenotype suggesting a protective role of the ascorbic acid in SEPN1 KO muscle. We also found that the highly active diaphragm muscle shows impaired force production and ER stress in SEPN1 KO mice and that the ablation of the ER stress mediator C/EBP homologous protein (CHOP) prevents diaphragm dysfunction and attenuates ER stress in SEPN1 KO mice.

Lipotoxicity, meaning an overload of fatty acids, is among the conditions able to trigger ER stress. By feeding SEPN1 KO mice with a high-fat diet, we observed that the myopathic phenotype is not only restricted to the diaphragm, but also to the hind limb muscles of SEPN1 KO mice. These mice developed myopathic features that were characterised by the insurgence of ER stress.

These findings suggest that ER stress is a novel pathogenic mechanism underlying SEPN1-RM and therefore reveal a therapeutic target for this disease, for which no treatment is currently available.

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