High-intensity interval training (treadmill) effects in myokines and endoplasmic reticulum stress of calf muscles in obese mice / Efectos del entrenamiento interválico de alta intensidad (trotadora) en miocinas y estrés del retículo endoplasmático de los músculos surales en ratones obesos

SUMMARY: Obesity is commonly associated with chronic tissue inflammation and skeletal muscle dysfunction. The study aimed to investigate the effects of High-Intensity Interval training (HIIT) on myokines and endoplasmic reticulum (ER) stress of diet- induced obese (DIO) mice. Three-month-old C57BL/6 male mice were fed a control (C) diet (n=20) or a high-fat (HF) diet (n=20) for 16 weeks. Then, half of the groups underwent HIIT (treadmill running) for an additional four weeks. HIIT increased calf muscles' contribution to BW (+24 %) and reduced weight gain in HF/HIIT than in HF (-120 %). Intramuscular fat accumulation was observed in HF and HF/ HIIT. Peak velocity was higher in HF/HIIT compared to HF (+26 %). Plasma insulin did not change, but glycemia was lower in HF/HIIT than in HF (-30 %). Fndc5 (+418 %) and Irisin (+72 %) were higher in HF/HIIT than in HF. Muscle Fgf21 was higher in HF/HIIT compared to HF (+30 %). In addition, NfKb (-53 %) and Tnfa (-63 %) were lower in HF/HIIT than in HF. However, Il1b (-86 %), Il6 (- 48 %), Il7 (-76 %), and Il15 (-21 %) were lower in HF/HIIT than in HF. Finally, HIIT reduced ER stress in HF/HIIT compared to HF: Atf4, -61 %; Chop, -61 %; Gadd45, -95 %. In conclusion, HIIT leads to weight loss and avoids muscle depletion. HIIT improves blood glucose, Irisin-Fndc5, and peak velocity. In addition, HIIT mitigates muscle inflammation and ER stress.

La obesidad es asociada comúnmente con inflamación tisular crónica y disfunción del músculo esquelético. El estudio tuvo como objetivo investigar los efectos del entrenamiento de intervalos de alta intensidad (HIIT) en las mioquinas y el estrés del retículo endoplásmico (ER) de ratones obesos inducidos por dieta (DIO). Se alimentó a ratones macho C57BL/6 de tres meses de edad con una dieta control (C) (n=20) o una dieta rica en grasas (HF) (n=20) durante 16 semanas. Luego, la mitad de los grupos se sometieron a HIIT (carrera en una trotadora) durante cuatro semanas más. HIIT aumentó la contribución de los músculos de la pantorrilla al BW (+24 %) y redujo el aumento de peso en HF/HIIT en HF (-120 %). Se observó acumulación de grasa intramuscular en HF y HF/HIIT. La velocidad máxima fue mayor en HF/HIIT en comparación con HF (+26 %). La insulina plasmática no cambió, pero la glucemia fue menor en HF/HIIT que en HF (-30 %). Fndc5 (+418 %) e Irisin (+72 %) fueron mayores en HF/HIIT que en HF. El Fgf21 muscular fue mayor en HF/ HIIT en comparación con HF (+30 %). Además, NfKb (-53 %) y Tnfa (-63 %) fueron menores en HF/HIIT que en HF. Sin embar- go, Il1b (-86 %), Il6 (-48 %), Il7 (-76 %) e Il15 (-21 %) fueron más bajos en HF/HIIT que en HF. Finalmente, HIIT redujo el estrés de RE en HF/HIIT en comparación con HF: Atf4, -61 %; Picar, - 61 %; Gadd45, -95 %. En conclusión, HIIT conduce a la pérdida de peso y evita el agotamiento muscular. HIIT mejora la glucosa en sangre, Irisin-Fndc5 y la velocidad máxima. Además, HIIT mitiga la inflamación muscular y el estrés ER.

Activación de sensores del estrés del retículo endoplásmico por dietas asociadas a enfermedades metabólicas y COVID-19 / Activation of endoplasmic reticulum stress sensors by metabolic disease-associated diets and COVID-19

El retículo endoplásmico es un organelo abundante, dinámico y sensor de energía. Sus abundantes membranas, rugosa y lisa, se encuentran distribuidas en diferentes proporciones dependiendo del linaje y requerimiento celular. Su función es llevar a cabo la síntesis de proteínas y lípidos, y es el almacén principal de Ca2+ intracelular. La sobrecarga calórica y la glucolipotoxicidad generada por dietas hipercalóricas provoca la alteración del retículo endoplásmico, activando la respuesta a proteínas mal plegadas (UPR, Unfolded Protein Response, por sus siglas en inglés) como reacción al estrés celular relacionado con el retículo endoplásmico y cuyo objetivo es restablecer la homeostasis del organelo al disminuir el estrés oxidante, la síntesis de proteínas y la fuga de Ca2+. Sin embargo, durante un estrés crónico, la UPR induce formación de especies reactivas de oxígeno, inflamación y apoptosis, exacerbando el estado del retículo endoplásmico y propagando un efecto nocivo para los demás organelos. Es por ello que el estrés del retículo endoplásmico se ha considerado un inductor del inicio y desarrollo de enfermedades metabólicas, incluido el agravamiento de COVID-19. Hasta el momento, existen pocas estrategias para reestablecer la homeostasis del retículo endoplásmico, las cuales son dirigidas a los sensores que desencadenan la UPR. Por tanto, se justifica con urgencia la identificación de nuevos mecanismos y terapias novedosas relacionadas con mitigar el impacto del estrés del retículo endoplásmico y las complicaciones asociadas.

The endoplasmic reticulum is an abundant, dynamic and energy-sensing organelle. Its abundant membranes, rough and smooth, are distributed in different proportions depending on the cell lineage and requirement. Its function is to carry out protein and lipid synthesis, and it is the main intracellular Ca2+ store. Caloric overload and glycolipotoxicity generated by hypercaloric diets cause alteration of the endoplasmic reticulum, activating the Unfolded Protein Response (UPR) as a reaction to cellular stress related to the endoplasmic reticulum and whose objective is to restore the homeostasis of the organelle by decreasing oxidative stress, protein synthesis and Ca2+ leakage. However, during chronic stress, the UPR induces reactive oxygen species formation, inflammation and apoptosis, exacerbating the state of the endoplasmic reticulum and propagating a deleterious effect on the other organelles. This is why endoplasmic reticulum stress has been considered an inducer of the onset and development of metabolic diseases, including the aggravation of COVID-19. So far, few strategies exist to reestablish endoplasmic reticulum homeostasis, which are targeted to sensors that trigger UPR. Therefore, the identif ication of new mechanisms and novel therapies related to mitigating the impact of endoplasmic reticulum stress and associated complications is urgently warranted.

Comparison of endoplasmic reticulum stress and mitochondrial biogenesis responses after 12 weeks of treadmill running and ladder climbing exercises in the cardiac muscle of middle-aged obese rats

The purpose of the present study was to compare the influence of aerobic exercise (AE) lasting 12 weeks to that of resistance exercise (RE) of the same duration on endoplasmic reticulum (ER) stress and mitochondrial biogenesis in the cardiac muscle of middle-aged obese rats. Obesity was induced in thirty 50-week-old male Sprague Dawley rats over 6 weeks by administration of a high-fat diet. The rats were then subjected to treadmill-running (AE) and ladder-climbing (RE) exercises 3 times per week for 12 weeks. Rats in the AE group showed significantly lower increases in body weight and intraperitoneal fat than those in the sedentary control (SC) group (P<0.05). The 12-week exercise regimes resulted in a significant increase in expression of mitochondrial biogenesis markers and levels of peroxisome proliferator-activated receptor gamma coactivator 1α in the cardiac muscle (P<0.05). Phosphorylation of PKR-like ER kinase, an ER stress marker, decreased significantly (P<0.05) after the exercise training. Although a trend for decreased C/EBP homologous protein (CHOP) expression was observed in both exercise groups, only the AE group had a statistically significant decrease (P<0.05). Levels of GRP78, an ER stress marker that protects cardiac muscle, did not significantly differ among the groups. Although only the AE group decreased body weight and fat mass, the two exercise regimes had similar effects on cardiac muscle with the exception of CHOP. Therefore, we suggest that both AE, which results in weight loss, and high-intensity RE, though not accompanied by weight loss, protect obese cardiac muscle effectively.

Adiponectin is protective against endoplasmic reticulum stress-induced apoptosis of endothelial cells in sepsis

Endoplasmic reticulum (ER) stress is a critical molecular mechanism involved in the pathogenesis of sepsis. Hence, strategies for alleviating this stress may be essential for preventing cardiovascular injuries under sepsis. Adiponectin is secreted by adipocytes and its levels are decreased in sepsis. The purpose of this study was to investigate the protective effects of adiponectin treatment on endothelial cells and its mechanism. Male Wistar rats underwent cecal ligation and puncture (CLP) before being treated with adiponectin (72 and 120 μg/kg). The levels of malondialdehyde (MDA) in plasma, histological structure, and apoptosis of endothelial cells were evaluated. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with adiponectin at 10 and 20 μg/mL for 24 h after stimulation by lipopolysaccharide (LPS). The levels of reactive oxygen species (ROS), ultrastructure, rate of apoptosis, the expression of inositol-requiring enzyme 1α (IRE1α) protein, and its downstream molecules (78 kDa glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP), and caspase-12) were detected. The results showed that the levels of MDA and ROS induced by CLP or LPS stimulation were increased. Furthermore, endothelial cell apoptosis was increased under sepsis. The IRE1α pathway was initiated, as evidenced by activated IRE1α, increased GRP78, and up-regulated CHOP and caspase-12 in HUVECs. Following treatment with adiponectin, the number of apoptotic endothelial cells was markedly decreased. These findings demonstrated that treatment with adiponectin decreased apoptosis of endothelial cells caused by sepsis by attenuating the ER stress IRE1α pathway activated by oxidative stress.

GRP78 levels, regional fat distribution and endometrial cáncer / Niveles de GRP78, distribución regional del tejido adiposo y cáncer endometrial

Background: The association of obesity with endometrial cancer is supported by the presence of endoplasmic reticulum (ER) stress in the adipocyte. Glucose-regulated protein 78 (GRP78) is a marker for ER stress. This protein is a central regulator of ER stress due to its major anti-apoptotic role. It plays an important role in tumor development, progression and chemoresistance. Aim: To look for an association between android and gynoid obesity, plasma GRP78 levels and endometrial cancer. Material and methods: Forty four patients with endometrial cancer aged 72 ± 6 years and 44 healthy women aged 55 ± 9 years were studied. Android and gynoid fat distribution were determined by dual X-ray absorptiometry and plasma GRP78 levels were measured. Results: GRP78 plasma levels were significantly higher in patients with endometrial cancer as compared to the control group. Android fat distribution had a positive correlation with plasma GRP78 levels (p<0.01). Gynoid fat had a negative correlation with plasma GRP78 levels (p<0.01). Conclusions: GRP78 levels are associated with the distribution of adipose tissue and are higher in patients with endometrial cancer.

Antecedentes: La asociación de obesidad con cáncer endometrial puede depender de la presencia de estrés del retículo endoplásmico (RE) en el adipocito. La proteína 78 regulada por glucosa (GRP78) es un marcador de estrés del RE. Esta proteína regula el estrés de RE gracias a su rol antiaopoptótico. Ella juega un rol en el desarrollo, progresión y quimio-resistencia de tumores. Objetivo: Buscar una asociación entre obesidad androide o ginoide, niveles plasmáticos de GRP78 y cáncer endometrial. Material y métodos: Se estudiaron 44 mujeres con cáncer endometrial de 72 ± 6 años and 44 mujeres sanas de 55 ± 9 años. La distribución androide o ginoide de la grasa fue determinada por densitometría radiológica de doble fotón (DEXA) y se midieron los niveles plasmáticos de GRP78. Resultados: Los niveles de GRP78 fueron significativamente más altos en mujeres con cáncer endometrial. Se observó una correlación positiva entre la distribución de grasa androide y los niveles de GRP78 (p< 0.01). Se observó una correlación negativa entre distribución de grasa ginoide y niveles de GRP78. Conclusiones: Los niveles de GRP78 se correlacionan con la distribución del tejido adiposo y son mayores en mujeres con cáncer endometrial.

Endoplasmic reticulum stress and renal lesion in mice with combination of high-fat diet and streptozotocin-induced diabetes

ABSTRACT PURPOSE : To investigate in the kidney the pathologic changes and expression of GRP78 and CHOP in the Kunming (KM) mice with combination of high-fat diet and streptozotocin-induced diabetes. METHODS : Sixty two male KM mice were randomly divided into a normal control (NC) group (n=20) and a high-fat diet (HFD) group (n=42). After a four-week dietary manipulation, the KM mice in the HFD group were injected intraperitoneally with streptozotocin to induce diabetes. After diabetic models were successfully established, the kidneys were excised and conserved for further test. RESULTS : No significant difference in the body weight was observed after the dietary manipulation (p=0.554). After the streptozotocin was injected, fasting blood glucose levels in the diabetes group (DM) were significantly higher than that in the NC group (p＜0.0001). Glomerular atrophy observed under light microscope in the DM group was more serious compared with the NC group. The expression of GRP78 and CHOP in the kidneys of the mice in the DM group were higher compared with the NC group. CONCLUSION : Renal lesion occurs in the diabetic Kunming mice induced by combination of high-fat diet and low-dose streptozotocin, and endoplasmic reticulum stress and CHOP may contribute to the injury process.

Effects of HO-1 on Lipopolysaccharide-induced Endoplasmic Reticulum Stress of Rat Hepatocytes / 法医学杂志

OBJECTIVE@#To investigate effects of antioxidant stress protein heme oxygenase-1 (HO-1) on lipopolysaccharide (LPS)-induced endoplasmic reticulum stress (ERS) of rat hepatocytes.@*METHODS@#The BRL cells (rat hepatocyte cell line) were cultured. The hepatocytes were treated with LPS, LPS+HO-1 siRNA, HO-1 siRNA and PBS solution, respectively. The cell viability was measured by trypan blue exclusion test. The apoptosis cells were detected by the fluorescent dye Hoechst 33258. Expressions of GRP78, CHOP, caspase-12 and HO-1 were detected by Western blotting.@*RESULTS@#LPS caused an increase of HO-1 protein expression of rat hepatocytes in a dose-dependent and time-dependent manner, a up-regulation of GRP78, CHOP and caspase-12, a decrease in cell viability, and an increase in apoptosis rate of hepatocytes. Pretreatment of HO-1 siRNA inhibited the up-regulation of LPS-induced HO-1, however, aggravated ERS and cellular injury.@*CONCLUSION@#HO-1 inhibites ERS-mediated cellular injury of rat hepatocytes induced by LPS.