Impaired functional exercise capacity and greater cardiovascular response to the 6-min walk test in congenital generalized lipodystrophy.

BACKGROUND: Congenital Generalized Lipodystrophy (CGL) is an ultra-rare disease characterized by metabolic disorders. However, the evaluation of functional exercise capacity, cardiovascular (CV) response to exercise, and peripheral arterial disease (PAD) in CGL is scarce. Here we evaluated the performance and CV response to exercise and their association with PAD in CGL compared to healthy individuals. METHODS: Twelve CGL and 12 healthy subjects matched for age and gender were included. Functional exercise capacity, CV response, and PAD were measured using the six-minute walk test (6MWT) and ankle-brachial index (ABI), respectively. RESULTS: At baseline, CGL subjects showed reduced predicted walked distance (6MWD) (p = 0.009) and increased heart rate (HR), systolic (SBP), and diastolic (DBP) pressures compared to healthy subjects (p < 0.05). Most CGL subjects presented normal ABI values (1.0 ≤ ABI ≤ 1.4). Only 25% (n = 3) had ABI ≤ 0.9. CGL subjects did not present changes in ABI and blood pressure 12 months after metreleptin (MLP) replacement, but they walked a greater 6MWD than baseline (p = 0.04). Further, 6MWD and right ABI measurements were positively correlated in CGL subjects (p = 0.03). Right ABI negatively correlated with glucose, triglycerides, and VLDL-c (p < 0.05). CONCLUSIONS: We observed that CGL subjects had lower functional exercise capacity and higher cardiovascular effort for similar performance of 6MWT, suggesting that strategies for decreasing exercise effort in this population should be essential. Furthermore, better physical performance was associated with high ABI in CGL. Additional studies are needed to clarify leptin's role in preserving functional exercise capacity in CGL.

Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies.

Lipodystrophy syndromes are a group of rare diseases related to the pathological impairment of adipose tissue and metabolic comorbidities, including dyslipidemia, diabetes, insulin resistance, hypoleptinemia, and hypoadiponectinemia. They can be categorized as partial or generalized according to the degree of fat loss, and inherited or acquired disorders, if they are associated with genetic mutations or are related to autoimmunity, respectively. Some types of lipodystrophies have been associated with changes in both redox and endoplasmic reticulum (ER) homeostasis as well as muscle dysfunction (MD). Although ER stress (ERS) has been related to muscle dysfunction (MD) in many diseases, there is no data concerning its role in lipodystrophies' muscle physiopathology. Here we focused on congenital lipodystrophies associated with ERS and MD. We also described recent advances in our understanding of the relationships among ERS, MD, and genetic lipodystrophies, highlighting the adiponectin-protective roles.

Changes in redox and endoplasmic reticulum homeostasis are related to congenital generalized lipodystrophy type 2.

CGL type 2 is a rare autosomal recessive syndrome characterized by an almost complete lack of body fat. CGL is caused by loss-of-function mutations in both alleles of the BSCL2 gene that codifies to seipin. Subjects often show hyperglycemia, decreased HDL-c, and hypoadiponectinemia. These laboratory findings are important triggers for changes in redox and ER homeostasis. Therefore, our aim was to investigate whether these intracellular mechanisms are associated with this syndrome. We collected blood from people from Northeastern Brazil with 0, 1, and 2 mutant alleles for the rs786205071 in the BSCL2 gene. Through the qPCR technique, we evaluated the expression of genes responsible for triggering the antioxidant response, DNA repair, and ER stress in leukocytes. Colorimetric tests were applied to quantify lipid peroxidation and to evaluate the redox status of glutathione, as well as to access the panorama of energy metabolism. Long extension PCR was performed to observe leukocyte mitochondrial DNA lesions, and the immunoblot technique to investigate plasma adiponectin concentrations. Subjects with the rs786205071 in both BSCL2 alleles showed increased transcription of NFE2L2, APEX1, and OGG1 in leukocytes, as well as high concentrations of malondialdehyde and the GSSG:GSH ratio in plasma. We also observed increase of mitochondrial DNA lesions and XBP1 splicing, as well as a decrease in adiponectin and HDL-c. Our data suggest the presence of lipid lesions due to changes in redox homeostasis in that group, associated with increased levels of mitochondrial DNA damage and transcriptional activation of genes involved with antioxidant response and DNA repair.

Impairment of respiratory muscle strength in Berardinelli-Seip congenital lipodystrophy subjects.

BACKGROUND: Berardinelli-Seip Congenital Generalized Lipodystrophy (BSCL) is an ultra-rare metabolic disease characterized by hypertriglyceridemia, hyperinsulinemia, hyperglycemia, hypoleptinemia, and diabetes mellitus. Although cardiovascular disturbances have been observed in BSCL patients, there are no studies regarding the Respiratory Muscle Strength (RMS) in this type of lipodystrophy. This study aimed to evaluate RMS in BSCL subjects compared with healthy subjects. METHODS: Eleven individuals with BSCL and 11 healthy subjects matched for age and gender were included in this study. The Maximum Inspiratory Pressure (MIP), Maximum Expiratory Pressure (MEP), and Peripheral Muscle Strength (PMS) were measured for three consecutive years. BSCL subjects were compared to healthy individuals for MIP, MEP, and PMS. Correlations between PMS and MIP were also analyzed. The genetic diagnosis was performed, and sociodemographic and anthropometric data were also collected. RESULTS: BSCL subjects showed significantly lower values for MIP and MEP (p <  0.0001 and p = 0.0002, respectively) in comparison to healthy subjects, but no changes in handgrip strength (p = 0.15). Additionally, we did not observe changes in MIP, MEP, and PMS two years after the first analysis, showing maintenance of respiratory dysfunction in BSCL subjects (p = 0.05; p = 0.45; p = 0.99). PMS and MIP were not correlated in these subjects (r = 0.56; p = 0.18). CONCLUSION: BSCL subjects showed lower respiratory muscle strength when compared with healthy subjects; however, PMS was not altered. These findings were maintained at similar levels during the two years of evaluation. Our data reveal the first association of BSCL with the development of respiratory muscle weakness.