Bloise 2020 Thyroid
|Bloise FF, Santos AT, Brito JT, Andrade CBV, Oliveira TS, Souza AF, Fontes KN, Silva JD, Blanco NG, Silva PL, Rocco PRM, Fliers E, Boelen A, da-Silva WS, Ortiga-Carvalho TM (2020) Sepsis impairs thyroid hormone signaling and mitochondrial function in the mouse diaphragm. Thyroid [Epub ahead of print].|
Abstract: Sepsis can cause the nonthyroidal illness syndrome (NTIS), resulting in perturbed thyroid hormone (TH) signaling and reduced thyroxine (T4) levels. TH is a major regulator of muscle function, via its influence on mitochondria. The present study aimed to evaluate the relationship among TH signaling, mitochondrial function and the antioxidant defense system in the diaphragms of septic mice.
Male C57Bl/6 mice were divided into two groups: cecal ligation and puncture (CLP) and sham. Twenty-four hours after surgery, plasma, diaphragms and livers were collected. TH metabolism and responses were analyzed by measuring mRNA expression of Dio1 in the liver, and Thra, Thrb, Dio2, Slc16a10 and Slc16a2 (encodes MCT 10 and 8), in the diaphragm. T4 plasma levels were measured by radioimmunoassay. Damage to diaphragm mitochondria was assessed by electron microscopy and qPCR, and function with oxygraphy. The diaphragm anti-oxidative defense system was examined by qPCR, analyzing Sod1, Sod2, Sod3, Gpx1 and Cat expression. The effect of TH replacement was tested by treating the mice with T4 and tri-iodothyronine (T3) (CLP+TH) after surgery.
CLP mice presented reduced total plasma T4 concentrations, as well as downregulated Dio1 and upregulated Il1b mRNA expression in the liver. CLP mice also displayed downregulated Thra, Thrb, Slc16a10 and Slc16a2 expression in the diaphragm, suggesting that TH signaling was compromised. The expression of Ppargc1a (encodes PGC1a) was downregulated, which correlated with the decrease in the number of total mitochondria, increase in the percentage of injured mitochondria, downregulation of respiratory chain complex 2 and 3 mRNA expression and reduced maximal respiration. Additionally, septic animals presented a 3-fold increase in Ucp3 and G6pdh expression, downregulated Sod3, Gpx1 and Cat expression; and upregulated Sod2 expression, potentially due to elevated ROS levels. The mitochondrial number and the percentage of injured mitochondrial were similar between sham and CLP+TH mice.
Sepsis induced responses consistent with NTIS, resulted in mitochondrial damage and functional impairment, and modulated the expression of key antioxidant enzymes in the diaphragm. Thus, impaired diaphragm function during sepsis seems to involve altered local TH signaling, mitochondrial dysfunction and oxidative stress defense.
• Keywords: Diaphragm, Mitochondria, Reactive Oxygen Species, Nonthyroidal Illness Syndrome, Thyroid Hormones, Sepsis, CLP, Oxidative Phosphorylation • Bioblast editor: Plangger M
Labels: MiParea: Respiration Pathology: Sepsis
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: N, CIV, NS HRR: Oxygraph-2k