bims-mifefi 2024-03-24 papers

bims-mifefi

Biomed News

on Mitochondria and female physiology

Issue of 2024–03–24
nineteen papers selected by
Kayla Vandiver, East Carolina University

Differential utilisation of subcellular skeletal muscle glycogen pools: a comparative analysis between 1 and 15 min of maximal exercise.
Endurance training increases mitochondrial myoglobin and enhances its interaction with complex IV in rat plantaris muscle.
Menopausal hormone therapy: A review of metabolic and thermogenic effects.
Proteomic Profiling of Muscular Adaptations to Short-term Concentric vs. Eccentric Exercise Training in Humans.
Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery.
Muscle-UCP3 in the regulation of energy metabolism.
Exercise intensity governs tumor control in mice with breast cancer.
Greater glycemic control following low-load, high-repetition resistance exercise compared with moderate-intensity continuous exercise in males and females: a randomized control trial.
Sex differences in mortality and liver-related events in non-alcoholic fatty liver disease: A systematic review and meta-analysis.
Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice.
Role of the gut microbiota in the pathogenesis of endometriosis: a review.
Time course changes in in vivo muscle mechanical function and Ca2+ regulation of force following experimentally induced gradual ovarian failure in mice.
Letrozole delays acquisition of water maze task in female BALB/c mice: Possible involvement of anxiety.
Cre-LoxP and tamoxifen-induced deletion of ovarian quiescin sulfhydryl oxidase 2 showed disruption of ovulatory activity in mice.
Adolescents diagnosed with polycystic ovary syndrome under the Rotterdam criteria but not meeting the diagnosis under the updated guideline.
Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1.
The Level of Sex Hormones and Corticosterone in Female Rats during Modeling of Visceral Obesity, Subsequent Physical Activity, and Normalization of the Diet.
Biomarkers identification in follicular fluid in relation to live birth in in vitro fertilization of women with polycystic ovary syndrome in different subtypes by using UPLC-MS method.
Jujuboside A Attenuates Polycystic Ovary Syndrome Based on Estrogen Metabolism Through Activating AhR-mediated CYP1A2 Expression.

J Physiol. 2024 Mar 19.

Differential utilisation of subcellular skeletal muscle glycogen pools: a comparative analysis between 1 and 15 min of maximal exercise.

Camilla Tvede Schytz, Niels Ørtenblad, Kasper Degn Gejl, Joachim Nielsen.

  In skeletal muscle, glycogen particles are distributed both within and between myofibrils, as well as just beneath the sarcolemma. Their precise localisation may influence their degradation rate. Here, we investigated how exercise at different intensities and durations (1- and 15-min maximal exercise) with known variations in glycogenolytic rate and contribution from anaerobic metabolism affects utilisation of the distinct pools. Furthermore, we investigated how decreased glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise affect the storage of glycogen particles (size, numerical density, localisation). Twenty participants were divided into two groups performing either a 1-min (n = 10) or a 15-min (n = 10) maximal cycling exercise test. In a randomised, counterbalanced, cross-over design, the exercise tests were performed following short-term consumption of two distinct diets with either high or moderate carbohydrate content (10 vs. 4 g kg-1 body mass (BM) day-1 ) mediating a difference in total energy consumption (240 vs. 138 g kg-1 BM day-1 ). Muscle biopsies from m. vastus lateralis were obtained before and after the exercise tests. Intermyofibrillar glycogen was preferentially utilised during the 1-min test, whereas intramyofibrillar glycogen was preferentially utilised during the 15-min test. Lowering carbohydrate and energy intake after glycogen-depleting exercise reduced glycogen availability by decreasing particle size across all pools and diminishing numerical density in the intramyofibrillar and subsarcolemmal pools. In conclusion, distinct subcellular glycogen pools were differentially utilised during 1-min and 15-min maximal cycling exercise. Additionally, lowered carbohydrate and energy consumption after glycogen-depleting exercise altered glycogen storage by reducing particle size and numerical density, depending on subcellular localisation. KEY POINTS: In human skeletal muscle, glycogen particles are localised in distinct subcellular compartments, referred to as intermyofibrillar, intramyofibrillar and subsarcolemmal pools. The intermyofibrillar and subsarcolemmal pools are close to mitochondria, while the intramyofibrillar pool is at a distance from mitochondria. We show that 1 min of maximal exercise is associated with a preferential utilisation of intermyofibrillar glycogen, and, on the other hand, that 15 min of maximal exercise is associated with a preferential utilisation of intramyofibrillar glycogen. Furthermore, we demonstrate that reduced glycogen availability achieved through lowering carbohydrate and energy intake after glycogen-depleting exercise is characterised by a decreased glycogen particle size across all compartments, with the numerical density only diminished in the intramyofibrillar and subsarcolemmal compartments. These results suggest that exercise intensity influences the subcellular pools of glycogen differently and that the dietary content of carbohydrates and energy is linked to the size and subcellular distribution of glycogen particles.

Keywords:  carbohydrate; fatigue; high-intensity exercise; performance; skeletal muscle fibres; subcellular glycogen; transmission electron microscopy

DOI:  https://doi.org/10.1113/JP285762
Acta Physiol (Oxf). 2024 Mar 21. e14139

Endurance training increases mitochondrial myoglobin and enhances its interaction with complex IV in rat plantaris muscle.

Rikuhide Koma, Tsubasa Shibaguchi, Tatsuya Yamada, Yudai Nonaka, Thomas Jue, Ayaka Yamazaki, Kazumi Masuda.

   AIM: Endurance exercise training is known to increase mitochondrial respiration in skeletal muscle. However, the molecular mechanisms behind this are not fully understood. Myoglobin (Mb) is a member of the globin family, which is highly expressed in skeletal and cardiac muscles. We recently found that Mb localizes inside mitochondria in skeletal muscle and interacts with cytochrome c oxidase subunit IV (COXIV), a subunit of mitochondrial complex IV, which regulates respiration by augmenting complex IV activity. In the present study, we investigated the effect of endurance training on Mb-COXIV interaction within mitochondria in rat skeletal muscle.
METHODS: Eight-week-old male Wistar rats were subjected to 6-week treadmill running training. Forty-eight hours after the last training session, the plantaris muscle was removed under anesthesia and used for biochemical analysis.
RESULTS: The endurance training increased mitochondrial content in the skeletal muscle. It also augmented complex IV-dependent oxygen consumption and complex IV activity in isolated mitochondria from skeletal muscle. Furthermore, endurance training increased Mb expression at the whole muscle level. Importantly, mitochondrial Mb content and Mb-COXIV binding were increased by endurance training.
CONCLUSION: These findings suggest that an increase in mitochondrial Mb and the concomitant enhancement of Mb interaction with COXIV may contribute to the endurance training-induced upregulation of mitochondrial respiration by augmenting complex IV activity.

Keywords:  mitochondrial localization; myoglobin; skeletal muscle

DOI:  https://doi.org/10.1111/apha.14139
Maturitas. 2024 Mar 12. pii: S0378-5122(24)00061-6. [Epub ahead of print] 107966

Menopausal hormone therapy: A review of metabolic and thermogenic effects.

Susanna Weidlinger, Petra Stute.



Keywords:  Brown adipose tissue; Menopausal hormone therapy; Metabolism; Obesity; Resting energy expenditure

DOI:  https://doi.org/10.1016/j.maturitas.2024.107966
Mol Cell Proteomics. 2024 Mar 15. pii: S1535-9476(24)00038-0. [Epub ahead of print] 100748

Proteomic Profiling of Muscular Adaptations to Short-term Concentric vs. Eccentric Exercise Training in Humans.

Jiawei Du, Hezhang Yun, Hongsheng Wang, Xin Bai, Yuhui Su, Xiaochuan Ge, Yang Wang, Boya Gu, Li Zhao, Ji-Guo Yu, Yafeng Song.

  The molecular mechanisms underlying muscular adaptations to concentric, and eccentric exercise training have been extensively explored. However, most previous studies have focused on subjectively selected proteins, thus, unable to provide a comprehensive protein profile, and potentially missing the crucial mechanisms underlying muscular adaptation to exercise training. We herein aimed to investigate proteomic profiles of human skeletal muscle in response to short-term resistance training. Twenty young males were randomly and evenly assigned to two groups to complete a four-week either eccentric (ECC) or concentric (CON) training program. Measurements of body composition and physiological function of the quadriceps femoris were conducted both before and after the training. Muscle biopsies from the vastus lateralis of randomly selected participants (five in ECC and four in CON) of both before- and after the training were analyzed using the liquid-chromatography tandem mass spectrometry (LC-MS/MS) in combination with bioinformatics analysis. Neither group presented a significant difference in body composition or leg muscle mass; however, muscle peak torque, total work, and maximal voluntary contraction were significantly increased after the training in both groups. Proteomics analysis revealed 122 differentially abundant proteins (DAPs; P value < 0.05 & Fold Change > 1.5 or < 0.67) in ECC, of which the increased DAPs were mainly related to skeletal muscle contraction and cytoskeleton, and enriched specifically in the pentose phosphate pathway, ECM-receptor interaction, and PI3K-Akt signaling pathway, whereas the decreased DAPs were associated with the mitochondrial respiratory chain. 101 DAPs were identified in CON, of which the increased DAPs were primarily involved in translation/protein synthesis and the mitochondria respiratory, whereas the decreased DAPs were related to metabolic processes, cytoskeleton, and de-ubiquitination. In conclusion, the four-week concentric- and eccentric training resulted in distinctly different proteomic profiles, especially in proteins related to muscular structure and metabolism.

Keywords:  Concentric exercise; Eccentric exercise; Human skeletal muscle; Proteomics; Short-term training

DOI:  https://doi.org/10.1016/j.mcpro.2024.100748
Sci Signal. 2024 Mar 19. 17(828): eadh2783

Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery.

Wing Suen Chan, Chun Fai Ng, Brian Pak Shing Pang, Miaojia Hang, Margaret Chui Ling Tse, Elsie Chit Yu Iu, Xin Ci Ooi, Xiuying Yang, Jason K Kim, Chi Wai Lee, Chi Bun Chan.

Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator-activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific Bdnf knockout (MBKO) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, MBKO mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.

DOI: https://doi.org/10.1126/scisignal.adh2783
Mitochondrion. 2024 Mar 16. pii: S1567-7249(24)00030-8. [Epub ahead of print] 101872

Muscle-UCP3 in the regulation of energy metabolism.

Lucio Della Guardia, Livio Luzi, Roberto Codella.

  Uncoupling protein-3 (UCP3) is a mitochondria-regulatory protein with potential energy- homeostatic functions. This study explores the role of UCP3 in the regulation of muscle- and energy metabolism. UCP3 is critical for tuning substrate utilization, favoring lipid oxidation, particularly in conditions of high-fat availability. While UCP3 is non-essential for lipid oxidation during energy excess, it proves vital during fasting, indicating an energy-homeostatic trait. Preliminary evidence indicates UCP3' promotion of glucose uptake and oxidation, at least in conditions of high glucose/low fat availability. However, the dynamics of how fats and glucose differentially influence UCP3 remain undefined. UCP3 exhibits inducible proton transport and uncoupling activity, operating in a dual manner: a resting state with no/low activity and an activated state in the presence of activators. Uncoupling may enhance thermogenesis in specific conditions and in the presence of activators such as fatty acids, thyroid hormones, and catecholamines. This energy-dissipative activity adapts to varying energy availability, balancing energy dissipation with fatty acid oxidation to optimize whole-body energy homeostasis: fasting triggers UCP3 upregulation, enhancing lipid utilization while suppressing uncoupling. Additionally, UCP3 upregulation induces glucose and lipid disposal from the bloodstream and decreases tri-/diglyceride storage in muscle. This process improves mitochondrial functionality and insulin signaling, leading to enhanced systemic gluco-metabolic balance and protection from metabolic conditions. Reviewed evidence suggests that UCP3 plays a crucial role in adapting the system to changing energy conditions. However, the precise role of UCP3 in regulating metabolism requires further elucidation.

Keywords:  Energy expenditure; Lipid oxidation; Metabolic diseases; Mitochondria; Thermogenesis; Uncoupling proteins

DOI:  https://doi.org/10.1016/j.mito.2024.101872
Front Immunol. 2024 ;15 1339232

Exercise intensity governs tumor control in mice with breast cancer.

Igor L Gomes-Santos, Ashwin S Kumar, Franziska Hausmann, Max N Meyer, Sarah Z Shiferaw, Zohreh Amoozgar, Rakesh K Jain, Dai Fukumura.

   Introduction: Exercise is recommended as an adjunct therapy in cancer, but its effectiveness varies. Our hypothesis is that the benefit depends on the exercise intensity.
Methods: We subjected mice to low intensity (Li), moderate intensity (Mi) or high intensity (Hi) exercise, or untrained control (Co) groups based on their individual maximal running capacity.
Results: We found that exercise intensity played a critical role in tumor control. Only Mi exercise delayed tumor growth and reduced tumor burden, whereas Li or Hi exercise failed to exert similar antitumor effects. While both Li and Mi exercise normalized the tumor vasculature, only Mi exercise increased tumor infiltrated CD8+ T cells, that also displayed enhanced effector function (higher proliferation and expression of CD69, INFγ, GzmB). Moreover, exercise induced an intensity-dependent mobilization of CD8+ T cells into the bloodstream.
Conclusion: These findings shed light on the intricate relationship between exercise intensity and cancer, with implications for personalized and optimal exercise prescriptions for tumor control.

Keywords:  CD8+ T cells; breast cancer; exercise; exercise intensity; immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1339232
Appl Physiol Nutr Metab. 2024 Mar 22.

Greater glycemic control following low-load, high-repetition resistance exercise compared with moderate-intensity continuous exercise in males and females: a randomized control trial.

Kayleigh M Beaudry, Julian C Surdi, Kristian Pancevski, Cory Tremblay, Michaela Devries-Aboud.

Exercise has long been known for its beneficial effects on insulin sensitivity (IS) and glucose handling with both moderate-intensity continuous (MIC) exercise and resistance exercise (RE) inducing beneficial effects. In recent years, low-load high repetition (LLHR) RE has emerged as a strategy to increase muscle mass and strength to levels similar to traditional RE, however the effects of LLHR RE on glucose handling has yet to be investigated. The purpose of this trial was to compare the acute effects of LLHR RE to MIC exercise on post-exercise glycemic control and insulin sensitivity in males and females. Twenty-four (n=12/sex) participants completed acute bouts of MIC exercise (30mins at 65% V̇O2peak) and LLHR (3 circuits, 6 exercises/circuit, 25-35 repetitions/exercise/circuit) matched for time with muscle biopsies immediately pre and post exercise and an oral glucose tolerance test (OGTT) 90 minutes following exercise. Blood glucose concentrations (p=0.002, ηp2=0.37), glucose AUC (p=0.002, ηp2=0.35) and max glucose concentration (p=0.003, ηp2=0.34) were lower during the post exercise OGTT following LLHR RE compared to MIC exercise. There was a main effect of trial on TBC1D1 Ser237 phosphorylation (p=0.04, ηp2=0.19) such that it was greater following MIC exercise compared to LLHR RE. Furthermore, phosphorylated ACC Ser79 increased following MIC exercise with no change following LLHR RE (p<0.001, ηp2=0.50). Phosphorylation of PTEN Ser380 was greater in males than females during LLHR RE (p=0.01, ηp2=0.27). These findings suggest that LLHR RE is a feasible exercise modality to improve post-exercise glycemic control in both males and females. Trial Registration Number: NCT06217679.

DOI: https://doi.org/10.1139/apnm-2023-0353
Liver Int. 2024 Mar 20.

Sex differences in mortality and liver-related events in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

Huimin Zhou, Haiyan Chen, Hanxiao Lu, Bo Wu, Shuo Zhang, Yuanlong Gu, Guangwen Zhou, Jie Xiang, Jun Yang.

   BACKGROUND & AIMS: Many systematic reviews explore the association of non-alcoholic fatty liver disease (NAFLD) with mortality, but none of them explores sex-based differences in detail. We aimed to assess whether NAFLD is associated with cause-specific mortality, all-cause mortality, and cancer incidence in both men and women.
METHODS: The PubMed, Embase, and Medline databases were searched from inception through April 2023 for eligible studies. We separately pooled relative risks (RRs) for men and women using a random effects model. Subsequently, the RRs and 95% CIs (confidence intervals) in each study were used to calculate the women-to-men ratio of RRs (RRR). Furthermore, subgroup analyses were performed to explore the robustness of outcomes. The random-effects model was employed to conduct sensitivity analyses to determine the impact of specific studies on the overall findings.
RESULTS: The meta-analysis included nine cohort studies comprising 557 614 patients with NAFLD were chosen. Women were 44% more likely than men to get cancer among those with NAFLD (RRR: 1.44; 95% CI: 1.02-2.04; p = .039). However, no sex-related differences were observed between NAFLD and all-cause mortality (RRR: 1.06; 95% CI: 0.56-2.01; p = .861), liver-related mortality (RRR: 1.06; 95% CI: 0.02-69.82; p = .977), cardiovascular mortality (RRR: 1; 95% CI: 0.65-1.53; p = .987) and liver cancer (RRR: 0.76; 95% CI: 0.43-1.36; p = .36).
CONCLUSIONS: There may be sex variations between NAFLD and the risk of cancer, with the connection being stronger in females than in males.

Keywords:  NAFLD; mortality; outcomes; sex difference

DOI:  https://doi.org/10.1111/liv.15910
Geroscience. 2024 Mar 19.

Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice.

Bianka Machado Zanini, Bianca Machado de Avila, Driele Neske Garcia, Jéssica Damé Hense, Gabriel Barreto Veiga, Mariana Machado Barreto, Sarah Ashiqueali, Jeffrey B Mason, Hariom Yadav, Michal Masternak, Augusto Schneider.

  The decline in the ovarian reserve leads to menopause and reduced serum estrogens. MicroRNAs are small non-coding RNAs, which can regulate gene expression and be secreted by cells and trafficked in serum via exosomes. Serum miRNAs regulate tissue function and disease development. Therefore, the aim of this study was to identify miRNA profiles in serum exosomes of mice induced to estropause and treated with 17β-estradiol (E2). Female mice were divided into three groups including control (CTL), injected with 4-Vinylcyclohexene diepoxide (VCD), and injected with VCD plus E2 (VCD + E2). Estropause was confirmed by acyclicity and a significant reduction in the number of ovarian follicles (p < 0.05). Body mass gain during estropause was higher in VCD and VCD + E2 compared to CTL females (p = 0.02). Sequencing of miRNAs was performed from exosomes extracted from serum, and 402 miRNAs were detected. Eight miRNAs were differentially regulated between CTL and VCD groups, seven miRNAs regulated between CTL and VCD + E2 groups, and ten miRNAs regulated between VCD and VCD + E2 groups. Only miR-200a-3p and miR-200b-3p were up-regulated in both serum exosomes and ovarian tissue in both VCD groups, suggesting that these exosomal miRNAs could be associated with ovarian activity. In the hepatic tissue, only miR-370-3p (p = 0.02) was up-regulated in the VCD + E2 group, as observed in serum. Our results suggest that VCD-induced estropause and E2 replacement have an impact on the profile of serum exosomal miRNAs. The miR-200 family was increased in serum exosomes and ovarian tissue and may be a candidate biomarker of ovarian function.

Keywords:  Aging; Estradiol; Menopause; Ovary; VCD

DOI:  https://doi.org/10.1007/s11357-024-01129-9
Front Microbiol. 2024 ;15 1363455

Role of the gut microbiota in the pathogenesis of endometriosis: a review.

Cuishan Guo, Chiyuan Zhang.

  Endometriosis is classically defined as a chronic inflammatory heterogeneous disorder occurring in any part of the body, characterized by estrogen-driven periodic bleeding, proliferation, and fibrosis of ectopic endometrial glands and stroma outside the uterus. Endometriosis can take overwhelmingly serious damage to the structure and function of multi-organ, even impair whole-body systems, resulting in severe dysmenorrhea, chronic pelvic pain, infertility, fatigue and depression in 5-10% women of reproductive age. Precisely because of a huge deficiency of cognition about underlying etiology and complex pathogenesis of the debilitating disease, early diagnosis and treatment modalities with relatively minor side effects become bottlenecks in endometriosis. Thus, endometriosis warrants deeper exploration and expanded investigation in pathogenesis. The gut microbiota plays a significant role in chronic diseases in humans by acting as an important participant and regulator in the metabolism and immunity of the body. Increasingly, studies have shown that the gut microbiota is closely related to inflammation, estrogen metabolism, and immunity resulting in the development and progression of endometriosis. In this review, we discuss the diverse mechanisms of endometriosis closely related to the gut microbiota in order to provide new approaches for deeper exploration and expanded investigation for endometriosis on prevention, early diagnosis and treatment.

Keywords:  endometriosis; estrogen; gut microbiota; immunity; inflammation

DOI:  https://doi.org/10.3389/fmicb.2024.1363455
Exp Physiol. 2024 Mar 18.

Time course changes in in vivo muscle mechanical function and Ca2+ regulation of force following experimentally induced gradual ovarian failure in mice.

Avery Hinks, Benjamin E Dalton, Parastoo Mashouri, Luke D Flewwelling, William Glen Pyle, Arthur J Cheng, Geoffrey A Power.

  The abrupt cessation of ovarian hormone release is associated with declines in muscle contractile function, yet the impact of gradual ovarian failure on muscle contractility across peri-, early- and late-stage menopause remains unclear. In this study, a 4-vinylcyclohexene diepoxide (VCD)-induced ovarian failure mouse model was used to examine time course changes in muscle mechanical function. Plantar flexors of female mice (VCD: n = 10; CON: n = 8) were assessed at 40 (early perimenopause), 80 (late perimenopause), 120 (menopause onset) and 176 (late menopause) days post-initial VCD injection. A torque-frequency relationship was established across a range of frequencies (10-200 Hz). Isotonic dynamic contractions were elicited against relative loads (10-80% maximal isometric torque) to determine the torque-velocity-power relationship. Mice then performed a fatigue task using intermittent 100 Hz isometric contractions until torque dropped by 60%. Recovery of twitch, 10 Hz and 100 Hz torque were tracked for 10 min post-task failure. Additionally, intact muscle fibres from the flexor digitorum brevis underwent a fatigue task (50 repetitions at 70 Hz), and 10 and 100 Hz tetanic [Ca2+ ] were monitored for 10 min afterward. VCD mice exhibited 16% lower twitch torque than controls across all time points. Apart from twitch torque, 10 Hz torque and 10 Hz tetanic [Ca2+ ], where VCD showed greater values relative to pre-fatigue during recovery, no significant differences were observed between control and VCD mice during recovery. These results indicate that gradual ovarian failure has minimal detriments to in vivo muscle mechanical function, with minor alterations observed primarily for low-frequency stimulation during recovery from fatigue.

Keywords:  VCD; menopause; muscle; ovarian hormones; ovaries; perimenopause; power

DOI:  https://doi.org/10.1113/EP091735
Horm Behav. 2024 Mar 20. pii: S0018-506X(24)00049-7. [Epub ahead of print]162 105524

Letrozole delays acquisition of water maze task in female BALB/c mice: Possible involvement of anxiety.

Jacek Mamczarz, Malcolm Lane, Istvan Merchenthaler.

  Letrozole, an aromatase inhibitor preventing estrogen synthesis from testosterone, is used as an adjuvant therapy in estrogen receptor-positive breast cancer patients. However, like other aromatase inhibitors, it induces many side effects, including impaired cognition. Despite its negative effect in humans, results from animal models are inconsistent and suggest that letrozole can either impair or improve cognition. Here, we studied the effects of chronic letrozole treatment on cognitive behavior of adult female BALB/c mice, a relevant animal model for breast cancer studies, to develop an appropriate animal model aimed at testing therapies to mitigate side effects of letrozole. In Morris water maze, letrozole 0.1 mg/kg impaired reference learning and memory. Interestingly, most of the letrozole 0.1 mg/kg-treated mice were able to learn the new platform position in reversal training and performed similar to control mice in a reversal probe test. Results of the reversal test suggest that letrozole did not completely disrupt spatial navigation, but rather delayed acquisition of spatial information. The delay might be related to increased anxiety as suggested by increased thigmotactic behavior during the reference memory training. The learning impairment was water maze-specific since we did not observe impairment in other spatial tasks such as in Y-maze or object location test. In contrast, the dose of 0.3 mg/kg did not have effect on water maze learning and facilitated locomotor habituation and recognition in novel object recognition test. The current study shows that letrozole dose-dependently modulates behavioral response and that its effects are task-dependent.

Keywords:  Aromatase inhibitor; Female BALB/c mice; Locomotor habituation; Recognition memory; Water maze learning

DOI:  https://doi.org/10.1016/j.yhbeh.2024.105524
J Ovarian Res. 2024 Mar 19. 17(1): 66

Cre-LoxP and tamoxifen-induced deletion of ovarian quiescin sulfhydryl oxidase 2 showed disruption of ovulatory activity in mice.

Shih-Yun Chen, Tse-En Wang, Wei-Yun Lee, Ya-Yi Yang, Hong-Chun Lai, Fuko Matsuda, Haruhiko Kosek, You-Tzung Chen, Sheng-Hsiang Li, Pei-Shiue Tsai.

   BACKGROUND: Quiescin sulfhydryl oxidase 2 (QSOX2) is a flavin adenine dinucleotide-dependent sulfhydryl oxidase that is known to be involved in protein folding, cell growth regulation, and redox state modification through oxidative activities. Earlier studies demonstrated the tissue and cellular localization of QSOX2 in the male reproductive tract, as well as the highly-regulated mechanism of QSOX2 protein synthesis and expression through the coordinated action of testosterone and epididymal-enriched amino acid, glutamate. However, the presence and the functions of QSOX2 in female reproduction are unknown. In this study, we applied the Cre-loxP gene manipulation system to generate the heterozygous and homozygous Qsox2 knockout mice and examined its effects on ovarian function.
RESULTS: We demonstrated that QSOX2 was detected in the follicle-supporting cells (granulosa and cumulus cells) of ovarian follicles of all stages but was absent in the corpus luteum, suggesting its supportive role in folliculogenesis. In comparison with reproductive organogenesis in wild-type mice, there was no difference in testicular and epididymal structure in male Qsox2 knockout; however, Qsox2 knockout disrupted the regular ovulation process in female mice as a drastic decrease in the formation of the corpus luteum was detected, and no pregnancy was achieved when mating males with homozygous Qsox2 knockout females. RNAseq analyses further revealed that Qsox2 knockout altered critical signaling pathways and genes that are responsible for maintaining ovarian functions.
CONCLUSION: Our data demonstrated for the first time that Qsox2 is critical for ovarian function in mice.

Keywords:  Estrogen; Female reproduction; Granulosa cells; Oocyte development; QSOX2

DOI:  https://doi.org/10.1186/s13048-024-01388-2
Hum Reprod. 2024 Mar 21. pii: deae042. [Epub ahead of print]

Adolescents diagnosed with polycystic ovary syndrome under the Rotterdam criteria but not meeting the diagnosis under the updated guideline.

Jin Ju Kim, Kyu Ri Hwang, Dayong Lee, Sunmie Kim, Young Min Choi.

   STUDY QUESTION: What are the characteristics of adolescents diagnosed with polycystic ovary syndrome (PCOS) based on the 2003 Rotterdam criteria, but who do not meet the diagnosis according to the international evidence-based guideline?
SUMMARY ANSWER: Adolescents who had features of PCOS but did not meet the evidence-based guideline adolescent criteria exhibited unfavorable metabolic profiles compared to controls and shared considerable metabolic and hormonal features with adolescents who did meet the adolescent criteria.
WHAT IS KNOWN ALREADY: The international evidence-based PCOS guideline recommended that ultrasound should not be used for the diagnosis of PCOS in girls with a gynecological age of <8 years. Thus far, few studies have evaluated the clinical characteristics of the girls diagnosed with PCOS based on the Rotterdam criteria but who do not meet the diagnosis according to the updated guideline.
STUDY DESIGN, SIZE, DURATION: This is a retrospective study, and subjects attended for care from 2004 to 2022.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Adolescent girls with PCOS diagnosed according to the 2003 Rotterdam criteria and healthy controls. All participants were between 2 and 8 years since menarche.
MAIN RESULTS AND THE ROLE OF CHANCE: Of the 315 girls diagnosed with PCOS according to the Rotterdam criteria, those with irregular menstruation (IM)/hyperandrogenism (HA)/polycystic ovary (PCO), IM/HA, HA/PCO, and IM/PCO phenotypes accounted for 206 (65.4%), 30 (9.5%), 12 (3.8%), and 67 (21.3%) participants, respectively. According to the evidence-based guideline, 79 girls (25.1%) with the HA/PCO or IM/PCO phenotypes were not diagnosed with PCOS, and aligned to the international guideline; they were designated as the 'at-risk' group. As expected, the girls meeting the evidence-based guideline adolescent criteria showed the worst metabolic profiles (degree of generalized or central obesity, frequency of insulin resistance, prediabetes or diabetes, and metabolic syndrome) and higher hirsutism scores than the at-risk group or controls. Approximately 90% of the at-risk group were not overweight or obese, which was similar to the controls. However, they showed worse metabolic profiles, with higher blood pressure, triglyceride, and insulin resistance parameters than controls; furthermore, these profiles were similar to those of the girls meeting the adolescent criteria. The at-risk group showed similarly elevated serum LH levels and LH/FSH ratio with the girls meeting adolescent criteria.
LIMITATIONS, REASONS FOR CAUTION: We could not evaluate hormonal or ultrasound parameters in controls.
WIDER IMPLICATIONS OF THE FINDINGS: Compared to the conventional Rotterdam criteria, the recent international evidence-based guideline-avoiding ultrasound in PCOS diagnosis in adolescents-still gives the opportunity to identify young girls at risk, aligned to the findings in this study. A practical approach to this adolescent population would involve establishing IM or HA (with ultrasound not indicated) and designating 'at-risk' PCOS status with regular check-ups for newly developed or worsening PCOS-related symptoms or metabolic abnormalities, with subsequent reassessment including ultrasound or anti-Müllerian hormone, once 8 years post-menarche.
STUDY FUNDING/COMPETING INTEREST(S): No funding was received in support of this study. The authors have no conflicts of interest to disclose.
TRIAL REGISTRATION NUMBER: N/A.

Keywords:  adolescent; anti-Müllerian hormone; diagnosis; hyperandrogenism; menstrual cycle irregularities; polycystic ovary syndrome

DOI:  https://doi.org/10.1093/humrep/deae042
Int J Obes (Lond). 2024 Mar 15.

Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1.

Peter Arner, Nathalie Viguerie, Lucas Massier, Mikael Rydén, Arne Astrup, Ellen Blaak, Dominique Langin, Daniel Peter Andersson.

BACKGROUND/OBJECTIVE: Insulin resistance is more prominent in men than women. If this involves adipose tissue is unknown and was presently examined.
SUBJECTS/METHODS: AdipoIR (in vivo adipose insulin resistance index) was measured in 2344 women and 787 men. In 259 of the women and 54 of the men, insulin induced inhibition of lipolysis (acylglycerol breakdown) and stimulation of lipogenesis (glucose conversion to acylglycerols) were determined in subcutaneous adipocytes; in addition, basal (spontaneous) lipolysis was also determined in the fat cells. In 234 women and 115 men, RNAseq expression of canonical insulin signal genes were measured in subcutaneous adipose tissue. Messenger RNA transcripts of the most discriminant genes were quantified in 175 women and 109 men.
RESULTS: Men had higher AdipoIR values than women but only when obesity (body mass index 30 kg/m2 or more) was present (p < 0.0001). The latter sex dimorphism was found among physically active and sedentary people, in those with and without cardiometabolic disease and in people using nicotine or not (p = 0.0003 or less). In obesity, adipocyte insulin sensitivity (half maximum effective hormone concentration) and maximal antilipolytic effect were tenfold and 10% lower, respectively, in men than women (p = 0.005 or less). Basal rate of lipolysis was two times higher in men than women (p > 0.0001). Sensitivity and maximum effect of insulin on lipogenesis were similar in both sexes (p = 0.26 and p = 0.18, respectively). When corrected for multiple comparison only RNAseq expression of insulin receptor substrate 1 (IRS1) was lower in men than women (p < 0.0001). The mRNA transcript for IRS1 was 60% higher in women than men (p < 0.0001).
CONCLUSIONS: In obesity, adipose tissue insulin resistance is more pronounced in men than in women. The mechanism involves less efficient insulin-mediated inhibition of adipocyte lipolysis, increased basal rate of lipolysis and decreased adipose expression of a key element of insulin signaling, IRS1.

DOI: https://doi.org/10.1038/s41366-024-01501-x
Bull Exp Biol Med. 2024 Mar 16.

The Level of Sex Hormones and Corticosterone in Female Rats during Modeling of Visceral Obesity, Subsequent Physical Activity, and Normalization of the Diet.

T A Mityukova, A A Basalai, O E Poluliakh, M A Darenskaya, L V Rychkova, S I Kolesnikov, N V Semenova, L I Kolesnikova.

  The effects of diet-induced visceral obesity and non-drug options of its correction on the level of sex hormones and corticosterone were evaluated in 84 female Wistar rats. During stage I, the rats received either a standard diet (STD) or a high-calorie diet (HCD) for 8 weeks. During stage II, the animals were divided into subgroups depending on obesity correction: without correction (STD control and HCD), transition from HCD to STD (HCD/STD) and/or physical activity (treadmill exercise) for the next 8 weeks (HCD/STD+exercise, STD+exercise, and HCD+exercise). Diet-induced visceral obesity resulted in hyperandrogenization and increased blood corticosterone levels in females. Transition from HCD to STD regardless of physical activity led to normalization of testosterone level and, accordingly, to return to the functional norm of estrogen-androgen balance. The positive effect of moderate physical activity on hormonal status is realized only against the background of a balanced diet or during the transition from HCD to STD.

Keywords:  corticosterone; modeling; rats; sex hormones; visceral obesity

DOI:  https://doi.org/10.1007/s10517-024-06057-4
Clin Chim Acta. 2024 Mar 18. pii: S0009-8981(24)00101-3. [Epub ahead of print]557 117860

Biomarkers identification in follicular fluid in relation to live birth in in vitro fertilization of women with polycystic ovary syndrome in different subtypes by using UPLC-MS method.

Xitong Liu, Chen Zhang, Jianlei Huang, Haiou Liu, Bo Li, Feifei Zhang, Congjian Xu.

   BACKGROUND: Polycystic ovary syndrome (PCOS) is a common infertility disorder which affects reproductive-aged women. However, metabolic change profiles of follicular fluid (FF) in lean and obese women diagnosed with and without PCOS remains unclear.
METHODS: 95 infertile women were divided into four subgroups: LC (lean control), OC (overweight control), LP (lean PCOS), and OP (overweight PCOS). The FF samples were collected during oocyte retrieval and assayed by ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) metabolomics.
RESULTS: A total of 236 metabolites were identified by metabolic analysis. The pathway enrichment analysis revealed that the glycerophospholipid metabolism (impact = 0.11182), ether lipid metabolism (impact = 0.14458), and primary bile acid biosynthesis (impact = 0.03267) were related to metabolic pathway between PCOS and control. Correlation analyses showed that epitestosterone sulfate was found positively correlated with fertilization rate in PCOS, while falcarindione, lucidone C. and notoginsenoside I was found to be negatively correlated. The combined four biomarkers including lucidone C, epitestosterone sulfate, falcarindione, and notoginsenoside I was better in predicting live birth rate, with AUC of 0.779.
CONCLUSION: The follicular fluid of women with PCOS showed unique metabolic characteristics. Our study provides better identification of PCOS follicular fluid metabolic dynamics, which may serve as potential biomarkers of live birth.

Keywords:  Biomarker; Follicular fluid; In vitro fertilization; Metabolomics; PCOS

DOI:  https://doi.org/10.1016/j.cca.2024.117860
Reprod Sci. 2024 Mar 18.

Jujuboside A Attenuates Polycystic Ovary Syndrome Based on Estrogen Metabolism Through Activating AhR-mediated CYP1A2 Expression.

Nan Zhou, Wenqiang Lv, Linna Chen, Kexin Chen, Qing He, Guangyan Xie, Jiachen Ma, Yijuan Cao, Bei Zhang, Xueyan Zhou.

  Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. This study aimed to investigate the therapeutic effects and mechanism of Jujuboside A on PCOS using a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Estrogen and androgen homeostasis was evaluated in serum from both clinical samples and PCOS mice. The stages of the estrous cycle were determined based on vaginal cytology. The ovarian morphology was observed by stained with hematoxylin and eosin. Moreover, we analyzed protein expression of cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and aryl hydrocarbon receptor (AhR) in ovary and KGN cells. Molecular docking, immunofluorescence, and luciferase assay were performed to confirm the activation of AhR by Jujuboside A. Jujuboside A effectively alleviated the disturbance of estrogen homeostasis and restored ovarian function, leading to an improvement in the occurrence and progression of PCOS. Furthermore, the protective effect of JuA against PCOS was dependent on increased CYP1A2 levels regulated by AhR. Our findings suggest that Jujuboside A improves estrogen disorders and may be a potential therapeutic agent for the treatment of PCOS.

Keywords:  Aryl hydrocarbon receptor; CYP1A2; Estrogen metabolism; Hormone homeostasis; Jujuboside A; Polycystic ovary syndrome

DOI:  https://doi.org/10.1007/s43032-024-01511-0