Endoplasmic Reticulum Stress in Respiratory Muscle Dysfunction of Congenital Generalized Lipodystrophy Subjects

Abstract

Congenital Generalized Lipodystrophy (CGL) was recently associated with Respiratory Muscle Dysfunction (RMD), as well as changes in redox homeostasis and endoplasmic reticulum stress (ERS). Although ERS has been related to RMD in many diseases, there is no data concerning its role in CGL physiopathology. We hypothesized that CGL-associated RMD may be related to oxidative stress (OS) and ERS. To evaluate the mRNA expression levels of OS and ERS factors, correlating with Maximal Respiratory Pressures in subjects with CGL. A cross-sectional study with 11 CGL subjects was conducted in Northeastern Brazil. NFE2L2, APEX1, OGG1, XBP1 splicing, DDIT3, and HSPA5 RNAm levels from CGL leukocytes were analyzed by qPCR. Gaussian distribution was evaluated by Shapiro Wilk and correlation tests were performed. The significance level was set at 5%. We found that the mean of NFE2L2, APEX1, and OGG1 RNAm levels was higher in CGL subjects compared to the healthy controls. Regarding ERS markers, we found that the mean of XBP1 RNAm levels was increased, while a significant reduction of DDIT3 RNAm was detected. Although no correlation was established between MIP and NFE2L2, APEX1, and OGG1 RNAm, a strong negative correlation was found between MIP and XBP1 RNAm splicing. Further, this ERS marker positively correlated with MEP. The upregulation of OS and ERS markers was observed in CGL subjects compared to the healthy controls. A strong negative correlation was only found between MIP and XBP1 splicing RNAm. These data suggest that CGL is an ERS-related metabolic disease and therapeutic strategies targeted to treat RMD in CGL should include ERS modulators.