Defects in TLR3 expression and RNase L activation lead to decreased MnSOD expression and insulin resistance in muscle cells of obese people

• Published in: Cell death & disease Vol. 5; no. 3; p. e1136
• Main Authors: Fabre, O, Breuker, C, Amouzou, C, Salehzada, T, Kitzmann, M, Mercier, J, Bisbal, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 2',5'-Oligoadenylate Synthetase - genetics; 2',5'-Oligoadenylate Synthetase - metabolism; 631/250/256; 631/80/86/2367; 692/699/2743/393; Animals; Antibodies; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biochemistry; Biochemistry, Molecular Biology; Biomedical and Life Sciences; Case-Control Studies; Cell Biology; Cell Culture; Down-Regulation; Endocrinology and metabolism; Endoribonucleases - genetics; Endoribonucleases - metabolism; Enzyme Activation; Female; Genomics; HeLa Cells; Human health and pathology; Humans; Immunology; Insulin - metabolism; Insulin Resistance; Life Sciences; Male; Mice; Middle Aged; Myoblasts, Skeletal - enzymology; Obesity - enzymology; Obesity - genetics; Original; original-article; Palmitic Acid - metabolism; Quadriceps Muscle - enzymology; RNA Interference; Signal Transduction; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Toll-Like Receptor 3 - genetics; Toll-Like Receptor 3 - metabolism; Transfection; latent endoribonuclease; manganese superoxide dismutase; toll-like receptor 3; inflammation; insulin response; obesity
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.104

Obesity is associated with chronic low-grade inflammation and oxidative stress that blunt insulin response in its target tissues, leading to insulin resistance (IR). IR is a characteristic feature of type 2 diabetes. Skeletal muscle is responsible for 75% of total insulin-dependent glucose uptake; consequently, skeletal muscle IR is considered to be the primary defect of systemic IR development. Interestingly, some obese people stay insulin-sensitive and metabolically healthy. With the aim of understanding this difference and identifying the mechanisms responsible for insulin sensitivity maintenance/IR development during obesity, we explored the role of the latent endoribonuclease (RNase L) in skeletal muscle cells. RNase L is a regulator of innate immunity, of double-stranded RNA sensors and of toll-like receptor (TLR) 4 signaling. It is regulated during inflammation by interferons and its activity is dependent on its binding to 2-5A, an oligoadenylate synthesized by oligoadenylate synthetases (OAS). Increased expression of RNase L or downregulation of its inhibitor (RLI) improved insulin response in mouse myogenic C2C12 cells and in primary human myotubes from normal-weight subjects treated with palmitate, a saturated free fatty acid (FFA) known to induce inflammation and oxidative stress
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TLR4 activation. While RNase L and RLI levels remained unchanged, OAS level was decreased in primary myotubes from insulin-resistant obese subjects (OB-IR) compared with myotubes from insulin-sensitive obese subjects (OB-IS). TLR3 and mitochondrial manganese superoxide dismutase (MnSOD) were also underexpressed in OB-IR myotubes. Activation of RNase L by 2-5A transfection allowed to restore insulin response, OAS, MnSOD and TLR3 expression in OB-IR myotubes. Due to low expression of OAS, OB-IR myotubes present a defect in RNase L activation and TLR3 regulation. Consequently, MnSOD level is low and insulin sensitivity is reduced. These results support that RNase L activity limits FFA/obesity-induced impairment of insulin response in muscle cells
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TLR3 and MnSOD expression.