Sex-specific transcriptome differences in a middle-aged frailty cohort.

BACKGROUND: Frailty is a clinical syndrome described as reduced physiological reserve and increased vulnerability. Typically examined in older adults, recent work shows frailty occurs in middle-aged individuals and is associated with increased mortality. Previous investigation of global transcriptome changes in a middle-aged cohort from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study demonstrated inflammatory genes and pathways were significantly altered by frailty status and race. Transcriptome differences in frailty by sex remain unclear. We sought to discover novel genes and pathways associated with sex and frailty in a diverse middle-aged cohort using RNA-Sequencing. METHODS: Differential gene expression and pathway analyses were performed in peripheral blood mononuclear cells for 1) frail females (FRAF, n = 4) vs non-frail females (NORF, n = 4), 2) frail males (FRAM, n = 4) vs non-frail males (NORM, n = 4), 3) FRAM vs FRAF, and 4) NORM vs NORF. We evaluated exclusive significant genes and pathways, as well as overlaps, between the comparison groups. RESULTS: Over 80% of the significant genes exclusive to FRAF vs NORF, FRAM vs NORM, and FRAM vs FRAF, respectively, were novel and associated with various biological functions. Pathways exclusive to FRAF vs NORF were associated with reduced inflammation, while FRAM vs NORM exclusive pathways were related to aberrant musculoskeletal physiology. Pathways exclusive to FRAM vs FRAF were associated with reduced cell cycle regulation and activated catabolism and Coronavirus pathogenesis. CONCLUSIONS: Our results indicate sex-specific transcriptional changes occur in middle-aged frailty, enhancing knowledge on frailty progression and potential therapeutic targets to prevent frailty.

Frailty in middle age is associated with frailty status and race-specific changes to the transcriptome.

Frailty is an aging-associated syndrome resulting from diminished capacity to respond to stressors and is a significant risk factor for disability and mortality. Although frailty is usually studied in old age, it is present in mid-life. Given the increases in mortality statistics among middle-aged Americans, understanding molecular drivers of frailty in a younger, diverse cohort may facilitate identifying pathways for early intervention. We analyzed frailty-associated, genome-wide transcriptional changes in middle-aged blacks and whites. Next generation RNA sequencing was completed using total RNA from peripheral blood mononuclear cells (n = 16). We analyzed differential gene expression patterns and completed a parametric analysis of gene set enrichment (PAGE). Differential gene expression was validated using RT-qPCR (n = 52). We identified 5,082 genes differentially expressed with frailty. Frailty altered gene expression patterns and biological pathways differently in blacks and whites, including pathways related to inflammation and immunity. The validation study showed a significant two-way interaction between frailty, race, and expression of the cytokine IL1B and the transcription factor EGR1. The glucose transporter, SLC2A6, the neutrophil receptor, FCGR3B, and the accessory protein, C17orf56, were decreased with frailty. These results suggest that there may be demographic dependent, divergent biological pathways underlying frailty in middle-aged adults.

Tropomyosin Receptor Kinase B Agonist, 7,8-Dihydroxyflavone, Improves Mitochondrial Respiration in Placentas From Obese Women.

Maternal obesity negatively impacts the placenta, being associated with increased inflammation, decreased mitochondrial respiration, decreased expression of brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TRKB). TRKB induction by 7,8-dihydroxyflavone (7,8-DHF) improves energy expenditure in an obesity animal model. We hypothesized that TRKB activation would improve mitochondrial respiration in trophoblasts from placentas of obese women. Placentas were collected from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI > 30) women at term following cesarean section delivery without labor. Cytotrophoblasts were isolated and plated, permitting syncytialization. At 72 hours, syncytiotrophoblasts (STs) were treated for 1 hour with 7,8-DHF (10 nM-10 M), TRKB antagonists (ANA-12 (10 nM-1 M), Cyclotraxin B (1 nM-1M)), or vehicle. Mitochondrial respiration was measured using the XF24 Extracellular Flux Analyzer. TRKB, MAPK, and PGC1α were measured using Western blotting. Maternal obesity was associated with decreased mitochondrial respiration in STs; however, 7,8-DHF increased basal, ATP-coupled, maximal, spare capacity, and nonmitochondrial respiration. A 10 µM dose of 7,8-DHF reduced spare capacity in STs from lean women, with no effect on other respiration parameters. 7,8-DHF had no effect on TRKB phosphorylation; however, there was a concentration-dependent decrease of p38 MAPK phosphorylation and increase of PGC1α in STs from obese, but not in lean women. TRKB antagonism attenuated ATP-coupled respiration, maximal respiration, and spare capacity in STs from lean and obese women. 7,8-DHF improves mitochondrial respiration in STs from obese women, suggesting that the obese phenotype in the placenta can be rescued by TRKB activation.

Maternal obesity alters brain derived neurotrophic factor (BDNF) signaling in the placenta in a sexually dimorphic manner.

INTRODUCTION: Obesity is a major clinical problem in obstetrics being associated with adverse pregnancy outcomes and fetal programming. Brain derived neurotrophic factor (BDNF), a validated miR-210 target, is necessary for placental development, fetal growth, glucose metabolism, and energy homeostasis. Plasma BDNF levels are reduced in obese individuals; however, placental BDNF has yet to be studied in the context of maternal obesity. In this study, we investigated the effect of maternal obesity and sexual dimorphism on placental BDNF signaling. METHODS: BDNF signaling was measured in placentas from lean (pre-pregnancy BMI < 25) and obese (pre-pregnancy BMI>30) women at term without medical complications that delivered via cesarean section without labor. MiRNA-210, BDNF mRNA, proBDNF, and mature BDNF were measured by RT - PCR, ELISA, and Western blot. Downstream signaling via TRKB (BDNF receptor) was measured using Western blot. RESULTS: Maternal obesity was associated with increased miRNA-210 and decreased BDNF mRNA in placentas from female fetuses, and decreased proBDNF in placentas from male fetuses. We also identified decreased mature BDNF in placentas from male fetuses when compared to female fetuses. Mir-210 expression was negatively correlated with mature BDNF protein. TRKB phosphorylated at tyrosine 817, not tyrosine 515, was increased in placentas from obese women. Maternal obesity was associated with increased phosphorylation of MAPK p38 in placentas from male fetuses, but not phosphorylation of ERK p42/44. DISCUSSION: BDNF regulation is complex and highly regulated. Pre-pregnancy/early maternal obesity adversely affects BDNF/TRKB signaling in the placenta in a sexually dimorphic manner. These data collectively suggest that induction of placental TRKB signaling could ameliorate the placental OB phenotype, thus improving perinatal outcome.