ER stress and ERO1: Potential therapeutic targets for inherited myopathies
Authors: Anirban Roy, Aniket S. Joshi, Ashok Kumar
Journal: Cell Reports Medicine (2024)

Selenoprotein N-related myopathy (SEPN1-RM) is a genetic disease that causes muscle weakness and respiratory failure. Germani et al.1Germani S. Ho A.T.V. Cherubini A. Varone E. Chernorudskiy A. Renna G.M. Fumagalli S. Gobbi M. Lucchetti J. Bolis M. et al.SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA.Cell Rep. Med. 2024; 5: 101439https://doi.org/10.1016/j.xcrm.2024.101439Google Scholar demonstrate that diaphragm weakness in SEPN1-RM is prevented by the inhibition of ER stress or ERO1 oxidoreductase regulated by transcription factor CHOP. Selenoprotein N-related myopathy (SEPN1-RM) is a genetic disease that causes muscle weakness and respiratory failure. Germani et al.1Germani S. Ho A.T.V. Cherubini A. Varone E. Chernorudskiy A. Renna G.M. Fumagalli S. Gobbi M. Lucchetti J. Bolis M. et al.SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA.Cell Rep. Med. 2024; 5: 101439https://doi.org/10.1016/j.xcrm.2024.101439Google Scholar demonstrate that diaphragm weakness in SEPN1-RM is prevented by the inhibition of ER stress or ERO1 oxidoreductase regulated by transcription factor CHOP. The inherited myopathies, which include congenital, mitochondrial, and metabolic myopathies and muscular dystrophy, are a large group of genetic diseases that primarily affect skeletal muscle tissue.2Cardamone M. Darras B.T. Ryan M.M. Inherited myopathies and muscular dystrophies.Semin. Neurol. 2008; 28: 250-259https://doi.org/10.1055/s-2008-1062269Google Scholar Selenoprotein N (SEPN1) is an endoplasmic reticulum (ER) resident protein that controls luminal calcium levels through the activation of the sarcoplasmic/ER calcium ATPase (SERCA) pump in a redox-dependent manner.3Marino M. Stoilova T. Giorgi C. Bachi A. Cattaneo A. Auricchio A. Pinton P. Zito E. SEPN1, an endoplasmic reticulum-localized selenoprotein linked to skeletal muscle pathology, counteracts hyperoxidation by means of redox-regulating SERCA2 pump activity.Hum. Mol. Genet. 2015; 24: 1843-1855https://doi.org/10.1093/hmg/ddu602Google Scholar,4Chernorudskiy A. Varone E. Colombo S.F. Fumagalli S. Cagnotto A. Cattaneo A. Briens M. Baltzinger M. Kuhn L. Bachi A. et al.Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity.Proc. Natl. Acad. Sci. USA. 2020; 117: 21288-21298https://doi.org/10.1073/pnas.2003847117Google Scholar SEPN1 is predominately enriched in the mitochondria-associated membrane (MAM) domains of the ER that regulate the flow of calcium between ER and mitochondria. Loss of function of SEPN1 results in a congenital myopathy known as SEPN1-related myopathy (SEPN1-RM).3Marino M. Stoilova T. Giorgi C. Bachi A. Cattaneo A. Auricchio A. Pinton P. Zito E. SEPN1, an endoplasmic reticulum-localized selenoprotein linked to skeletal muscle pathology, counteracts hyperoxidation by means of redox-regulating SERCA2 pump activity.Hum. Mol. Genet. 2015; 24: 1843-1855https://doi.org/10.1093/hmg/ddu602Google Scholar Patients with SEPN1-RM demonstrate specific clinical features, such as neck and trunk muscle atrophy, scoliosis, and diaphragm weakness that eventually leads to respiratory failure.5Villar-Quiles R.N. von der Hagen M. Métay C. Gonzalez V. Donkervoort S. Bertini E. Castiglioni C. Chaigne D. Colomer J. Cuadrado M.L. et al.The clinical, histologic, and genotypic spectrum of SEPN1-related myopathy: A case series.Neurology. 2020; 95: e1512-e1527https://doi.org/10.1212/WNL.0000000000010327Google Scholar Beyond palliative care, there is currently no approved therapy for SEPN1-RM, presumably because the molecular underpinnings for unusual weakness of the diaphragm and other muscles remain completely unknown. In addition to serving as a Ca2+ reservoir, the ER is also a major site for protein synthesis and folding. Under certain conditions, the demand for protein synthesis increases dramatically, which exceeds the protein-folding capacity of the ER lumen, resulting in the accumulation of misfolded or unfolded proteins—a state commonly known as ER stress.6Afroze D. Kumar A. ER stress in skeletal muscle remodeling and myopathies.FEBS J. 2019; 286: 379-398https://doi.org/10.1111/febs.14358Google Scholar To alleviate stress and restore ER function, cells initiate a signaling cascade referred to as the unfolded protein response (UPR). The UPR is mediated by three ER transmembrane sensors: protein kinase R-like ER kinase (PERK), activating transcription factor 6, and inositol-requiring protein 1α. The main function of the UPR is to restore proteostasis through reducing protein translation while augmenting synthesis of chaperones that would augment protein folding. However, chronic unmitigated ER stress induces prolonged activation of the UPR, termed "maladaptive UPR," which leads to various pathological states, such as insulin resistance, inflammation, and cell death.7Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond.Nat. Rev. Mol. Cell Biol. 2012; 13: 89-102https://doi.org/10.1038/nrm3270Google Scholar Accumulating evidence suggests that the markers of ER stress and the UPR are upregulated in various types of myopathies and other neuromuscular disorders.6Afroze D. Kumar A. ER stress in skeletal muscle remodeling and myopathies.FEBS J. 2019; 286: 379-398https://doi.org/10.1111/febs.14358Google Scholar It has been suggested that in the absence of SEPN1 protein, the ER stress response becomes maladaptive, which results in the inhibition of SERCA activity. This phenomenon is attributed to the increased expression of ER oxidoreductin 1 (ERO1), a protein disulfide oxidase and H2O2 producer8Zito E. ERO1: A protein disulfide oxidase and H2O2 producer.Free Radic. Biol. Med. 2015; 83: 299-304https://doi.org/10.1016/j.freeradbiomed.2015.01.011Google Scholar that is regulated by the transcription factor C/EBP homologous protein (CHOP).9Pozzer D. Varone E. Chernorudskiy A. Schiarea S. Missiroli S. Giorgi C. Pinton P. Canato M. Germinario E. Nogara L. et al.A maladaptive ER stress response triggers dysfunction in highly active muscles of mice with SELENON loss.Redox Biol. 2019; 20: 354-366https://doi.org/10.1016/j.redox.2018.10.017Google Scholar In the current study published in Cell Reports Medicine, Germani et al.1Germani S. Ho A.T.V. Cherubini A. Varone E. Chernorudskiy A. Renna G.M. Fumagalli S. Gobbi M. Lucchetti J. Bolis M. et al.SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA.Cell Rep. Med. 2024; 5: 101439https://doi.org/10.1016/j.xcrm.2024.101439Google Scholar demonstrate that ERO1 is upregulated in preclinical models of SEPN1-RM. Intriguingly, SEPN1 associates covalently with ERO1 in a redox-dependent manner. The interaction between SEPN1 and ERO1 promotes oligomerization of SEPN1, which diminishes SEPN1's redox trapping potential. Loss of SEPN1 reduces short-distance MAMs, with concomitant increase in ER stress and ERO1 expression. Treatment with ERO1 inhibitor EN460 or chemical chaperone tauroursodeoxycholic acid (TUDCA, a pan-inhibitor of ER stress) rescues short-distance MAMs and improves viability of SEPN1 knockout (KO) cells. Similarly, SEPN1 and ERO1 double knockout (DKO) cells show improvements in short-distance MAMs in comparison to SEPN1 KO cells, further suggesting that the inhibition of ERO1 activity rescues the deleterious effects of the loss of SEPN1 in cultured cells. Using genetic mouse models, the authors also demonstrate that various markers of ER stress are considerably reduced, whereas oxidative phosphorylation and ATP levels are upregulated, in the diaphragms of SEPN1 and ERO1 DKO mice compared to SEPN1 KO mice. Moreover, disruption in mitochondria localization and association with ER Ca2+ release unit (CRU) as well as muscle dysfunction observed in skeletal muscle of SEPN1 KO mice are significantly rescued in DKO mice. Similarly, chronic treatment with TUDCA reduces ER stress and ERO1 levels in diaphragm, rescues CRU/mitochondria couples, and improves calcium dynamics and muscle force production in SEPN1 KO mice. In addition, the authors demonstrate that in comparison to healthy controls, levels of ER stress markers, including ERO1, are significantly upregulated in SEPN1-RM patient myoblasts, and treatment with TUDCA improves ATP levels in these myoblasts.1Germani S. Ho A.T.V. Cherubini A. Varone E. Chernorudskiy A. Renna G.M. Fumagalli S. Gobbi M. Lucchetti J. Bolis M. et al.SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA.Cell Rep. Med. 2024; 5: 101439https://doi.org/10.1016/j.xcrm.2024.101439Google Scholar Altogether, the study suggests that the loss of SEPN1 results in ER stress and ERO1 activation, which cause oxidative stress, bioenergetics defects, and impairment of SERCA function that lead to diaphragm weakness and myopathy (Figure 1). The role of adaptive and maladaptive UPR has been previously investigated in preclinical models of many other degenerative diseases.7Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond.Nat. Rev. Mol. Cell Biol. 2012; 13: 89-102https://doi.org/10.1038/nrm3270Google Scholar While the UPR is activated in skeletal muscle in both physiological and pathophysiological conditions,6Afroze D. Kumar A. ER stress in skeletal muscle remodeling and myopathies.FEBS J. 2019; 286: 379-398https://doi.org/10.1111/febs.14358Google Scholar,10Wu J. Ruas J.L. Estall J.L. Rasbach K.A. Choi J.H. Ye L. Boström P. Tyra H.M. Crawford R.W. Campbell K.P. et al.The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex.Cell Metab. 2011; 13: 160-169https://doi.org/10.1016/j.cmet.2011.01.003Google Scholar it remains enigmatic whether its activation is a protective mechanism or causes deleterious consequences. The present study by Germani et al.1Germani S. Ho A.T.V. Cherubini A. Varone E. Chernorudskiy A. Renna G.M. Fumagalli S. Gobbi M. Lucchetti J. Bolis M. et al.SEPN1-related myopathy depends on the oxidoreductase ERO1 alpha and is druggable with the chemical chaperone TUDCA.Cell Rep. Med. 2024; 5: 101439https://doi.org/10.1016/j.xcrm.2024.101439Google Scholar has delineated a novel molecular mechanism by which maladaptive UPR causes muscle weakness in SEPN1-RM. The study further suggests that TUDCA, an FDA-approved drug, can potentially be repurposed for the treatment of SEPN1-RM patients. In future, it will be interesting to investigate whether inhibition of ER stress using chemical chaperones can also alleviate myopathy and provide functional gain in other types of inherited myopathies and muscular dystrophy. This work was supported by the National Institutes of Health grants AR081487 and AR059810 to A.K. The authors declare no competing interests.