Excessive Endoplasmic Reticulum Stress Correlates with Impaired Mitochondrial Dynamics, Mitophagy and Apoptosis, in Liver and Adipose Tissue, but Not in Muscles in EMS Horses

Abstract

Nowadays, endocrine disorders have become more frequent in both human and veterinary medicine. In horses, reduced physical activity combined with carbohydrate and sugar overload may result in the development of the so-called equine metabolic syndrome (EMS). EMS is characterized by insulin resistance, hyperinsulinemia, elevated blood triglyceride concentrations and usually obesity. Although the phenotypic features of EMS individuals are well known, the molecular mechanism underlying disease development remains elusive. Therefore, in the present study, we analyzed insulin-sensitive tissues, i.e., muscles, liver and adipose tissue in order to evaluate insulin resistance and apoptosis. Furthermore, we assessed mitochondrial dynamics and mitophagy in those tissues, because mitochondrial dysfunction is linked to the development of metabolic syndrome. We established the expression of genes related to insulin resistance, endoplasmic reticulum (ER) stress and mitochondria clearance by mitophagy using RT-PCR and Western blot. Cell ultrastructure was visualized using electron transmission microscopy. The results indicated that adipose tissue and liver of EMS horses were characterized by increased mitochondrial damage and mitophagy followed by triggering of apoptosis as mitophagy fails to restore cellular homeostasis. However, in muscles, apoptosis was reduced, suggesting the existence of a protective mechanism allowing that tissue to maintain homeostasis.

5‐Azacytydine and resveratrol reverse senescence and ageing of adipose stem cells via modulation of mitochondrial dynamics and autophagy

“…In our previous study, we have shown increased expression of IL‐6 and TNF‐α in adipose tissue and serum of Welsh ponies suffering from EMS. Similarly, many other authors have described increased levels of pro‐inflammatory cytokines, including IL‐1 β, IL‐6 and TNF‐α in serum and adipose tissue in EMS individuals It has been shown that TNF‐α is directly implicated in IR development by interfering with insulin signalling . This adverse microenvironment of adipose tissue negatively affects adipose stem cell population (ASC) residing within it.…”

“…Regional adiposity, obesity, hyperinsulinemia, insulin resistance (IR) and laminitis or susceptibility to laminitis are the major characteristics of equine metabolic syndrome (EMS) . It is worth noting that recent data have indicated that obesity should not be used as a diagnostic criterion EMS is a complex disorder involving alternation in metabolism and chronic systemic inflammation . However, due to its complexity, understanding EMS pathophysiology is still elusive.…”

Early feeding of rainbow trout (Oncorhynchus mykiss) with methionine deficient diet over a two-week period: consequences for liver mitochondria in juveniles

“…Mitochondria and ER form structural and functional networks that are essential in the maintenance of cellular homeostasis and in the determination of cell fate under various physiological conditions (Marchi et al, 2014;Szymanśki et al, 2017). ER stress can be transmitted to mitochondria through alterations in the transfer of metabolites such as Ca 2+ or through stress-sensitive signalling pathways that directly control mitochondrial integrity and mitophagy (Bouman et al, 2011;Guo et al, 2018;Kim et al, 2006;Marycz et al, 2018;Rainbolt et al, 2014;Senft and Ronai, 2015). In this regard, it is now well recognized that mitophagy is induced by the UPR during ER stress, in order to eliminate stress-damaged mitochondria and to protect cells from apoptosis (Kim et al, 2006;Maiuri et al, 2007), as noted above.…”

The endoplasmic reticulum stress induced by tunicamycin affects the viability and autophagy activity of chondrocytes

“…Margariti et al 15 also found that XBP1 mRNA splicing triggers an autophagic response in endothelial cells (ECs) through the transcriptional regulation of Beclin‐1. Moreover, the correlation between ER stress and mitophagy was reported in liver tissue and also shown to have a role in the chondrogenic and osteogenic differentiation of adipose stem cells in equine metabolic syndrome 16–18 . However, these previous studies used neoplastic cells, endothelial cells, or other cells types for their research.…”