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(SEPN1) Protects Skeletal Muscle from Saturated Fatty Acid-Induced ER

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(SEPN1) Protects Skeletal Muscle from Saturated Fatty Acid-Induced ER SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance Ersilia Varone, Diego Pozzer, Simona Di Modica, Alexander Chernorudskiy, Leonardo Nogara, Martina Baraldo, Mario Cinquanta, Stefano Fumagalli, Rocio Nur Villar-Quiles, Maria-Grazia de Simoni, et al. To cite this version: Ersilia Varone, Diego Pozzer, Simona Di Modica, Alexander Chernorudskiy, Leonardo Nogara, et al.. SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance. Redox Biology, Elsevier, 2019, 24, pp.101176. 10.1016/j.redox.2019.101176. hal- 02165757 HAL Id: hal-02165757 https://hal.sorbonne-universite.fr/hal-02165757 Submitted on 26 Jun 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Redox Biology 24 (2019) 101176 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox SELENON (SEPN1) protects skeletal muscle from saturated fatty acid- induced ER stress and insulin resistance T Ersilia Varonea,1, Diego Pozzera,1, Simona Di Modicaa, Alexander Chernorudskiya, Leonardo Nogarab,c, Martina Baraldob,c, Mario Cinquantad, Stefano Fumagallie, ∗ Rocio Nur Villar-Quilesf, Maria-Grazia De Simonie, Bert Blaauwb,c, Ana Ferreirof, Ester Zitoa, a Dulbecco Telethon Institute at Istituto di Ricerche Farmacologiche Mario Negri, IRCCS, Milan, Italy b Department of Biomedical Sciences, University of Padua, Padua, Italy c Venetian Institute of Molecular Medicine, Padua, Italy d Cogentech Società Benefit srl, at IFOM, Via Adamello, Milan, Italy e Istituto di Ricerche Farmacologiche Mario Negri, IRCCS, Milan, Italy f Pathophysiology of Striated Muscles laboratory, Unit of Functional and Adaptive Biology, BFA, University Paris Diderot/CNRS, Sorbonne Paris Cité, Paris, France - AP- HP, Centre de Référence Maladies Neuromusculaires Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France ARTICLE INFO ABSTRACT Keywords: Selenoprotein N (SELENON) is an endoplasmic reticulum (ER) protein whose loss of function leads to a con- Insulin resistance genital myopathy associated with insulin resistance (SEPN1-related myopathy). The exact cause of the insulin ER stress response resistance in patients with SELENON loss of function is not known. Skeletal muscle is the main contributor to SELENON insulin-mediated glucose uptake, and a defect in this muscle-related mechanism triggers insulin resistance and SEPN1 glucose intolerance. We have studied the chain of events that connect the loss of SELENON with defects in Congenital myopathies insulin-mediated glucose uptake in muscle cells and the effects of this on muscle performance. Here, we show that saturated fatty acids are more lipotoxic in SELENON-devoid cells, and blunt the insulin-mediated glucose uptake of SELENON-devoid myotubes by increasing ER stress and mounting a maladaptive ER stress response. Furthermore, the hind limb skeletal muscles of SELENON KO mice fed a high-fat diet mirrors the features of saturated fatty acid-treated myotubes, and show signs of myopathy with a compromised force production. These findings suggest that the absence of SELENON together with a high-fat dietary regimen increases susceptibility to insulin resistance by triggering a chronic ER stress in skeletal muscle and muscle weakness. Importantly, our findings suggest that environmental cues eliciting ER stress in skeletal muscle (such as a high-fat diet) affect the pathological phenotype of SEPN1-related myopathy and can therefore contribute to the assessment of prognosis beyond simple genotype-phenotype correlations. 1. Introduction Insulin signal transduction is activated in skeletal muscle following the binding of insulin to insulin receptor tyrosine kinase. The activated SELENON is localised in the endoplasmic/sarcoplasmic reticulum receptor phosphorylates the downstream docking protein substrates (ER/SR), has a thioredoxin reductase-like domain on the ER side of its which, as a result of phosphatidylinositol 3-kinase and Akt pathway sequence, and regulates ER calcium levels by means of the redox reg- activation, leads to the translocation of the GLUT4 glucose transporter ulating SERCA2 pump [1–3]. Despite its ubiquitous expression, SE- to the plasma membrane and cellular glucose uptake [6]. LENON loss of function gives rise to a selective muscle pathological Long-chain saturated fatty acid accumulation is lipotoxic in skeletal phenotype associated with insulin resistance [4]. As the majority of muscle [7,8] and induces ER stress, the consequent ER stress response insulin-dependent glucose uptake (75–90%) takes place in skeletal [9] that together with mitochondrial dysfunction contributes to the muscle, a defect in skeletal muscle insulin-dependent glucose disposal is pathogenesis of the muscle insulin resistance by inhibiting glucose widely viewed as being critical for the development of whole-body transport [10–12]. ER and mitochondria communicate through the insulin resistance and type 2 diabetes [5]. mitochondria associated membranes (MAMs), the disruption of which ∗ Corresponding author. IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milano, Italy. E-mail address: [email protected] (E. Zito). 1 These authors contributed equally to the study. https://doi.org/10.1016/j.redox.2019.101176 Received 6 February 2019; Received in revised form 4 March 2019; Accepted 20 March 2019 Available online 23 March 2019 2213-2317/ © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). E. Varone, et al. Redox Biology 24 (2019) 101176 also triggers insulin resistance by inducing ER stress and affecting mi- tochondrial metabolism [13–15]. We here show that the lack of SELENON in saturated fatty acid- challenged myotubes blunts insulin-dependent glucose uptake (i.e. triggers insulin resistance) by eliciting ER stress, disrupting ER-to-mi- tochondria communications, and altering mitochondria quality and cell bioenergetics. Importantly, SELENON KO mice fed a high-fat diet are < 6 UK 43 Normal 8 M more glucose intolerant, and their skeletal muscles show impaired in- c.1A > G (p.M1V) + c.565C > T (p.R189*) sulin signalling, strength force, and an increased ER stress. A combi- nation of SELENON loss and a high-fat diet therefore synergistically contribute to the pathogenesis of SEPN1-related myopathy by trig- 29.9: overweight; > 30: obese). UK: gering insulin resistance and impairing muscle performance. – 2. Results 2.1. Insulin resistance is part of the phenotype in SEPN1-related myopathy 16.6 34 Normal 4.6 7 M patients c.1358G > C (p.W453S) + c.1397G > A (p.R466Q) Autosomal recessive mutations of the SELENON gene (also known as 24.9: healthy weight; 25 SEPN1) cause SEPN1-related myopathy, a rare congenital myopathy – typically associated with low body mass index (BMI) [16]. Insulin re- sistance was first reported in 5 SEPN1-related myopathy patients in fi < 6 15.6 17 6 F Normal 2006 [4]. To con rm the association between SELENON defects and c.713dupA (p.N238Kfs*63) homozygous insulin resistance, we evaluated retrospectively follow-up data from eight patients with confirmed SELENON mutations in whom an oral glucose tolerance test (OGTT) had been performed. All patients had congenital muscle weakness more severe in axial muscles, respiratory insufficiency and scoliosis, typical of SEPN1-related myopathy. The < 6 18 28 5 M c.997_1000del (p.V333Pfs*6) homozygous results of the OGTT, summarized in Table 1, disclosed abnormal glucose Normal metabolism in 4 of the 8 patients, despite a very low body mass index (< 13.1). Patient 1 showed high level of fasting glycemia, without any increase in glycated hemoglobin. Patients 2–4 had normal basal gly- cemia but altered OGTT. Interestingly, Patient 1 evolved from normal 13 47 4 F c.13_22dup (p.Q8Pfs*78) homozygous 4.9 fasting blood glucose and OGGT at age of 37 years to basal hypergly- Increased 2 h plasma glucose (9.9 mmol/L) cemia one year later, stressing the need for regular controls of glucose metabolism during the follow-up of SEPN1-related myopathy patients. There was no correlation between abnormal glucose metabolism and patient age or with the type of SELENON mutation (truncating, non- sense or missense). In contrast, insulin-resistance or prediabetes were observed only in patients with extremely low BMI values. These results confirm that paradoxical insulin resistance in very low BMI patients is part of the SEPN1-related myopathy phenotype. 13.1 52 3 F c.13_22dup (p.Q8Pfs*78) + c.883G > A (p.E295K) Increased 1 h and 2glucose h (12.3 plasma and 9.8 mmol/L). Increased 2 h insulin (37.74mU/ L) 2.2. SELENON signal is clustered in response to a palmitate challenge 4.6 6 mmol/L); OGTT: Oral glucose tolerance test (reference values: 1 h post-load plasma insulin < 80 mU/L, 2 h post-load plasma insulin < 14 mU/L, 1 h We moved to a cell system to study the chain of events that connect – SELENON loss with an insulin resistant phenotype. In order to over-
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