scholarly journals Sex Differences in Constitutive Autophagy

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Sara Oliván ◽  
Ana Cristina Calvo ◽  
Raquel Manzano ◽  
Pilar Zaragoza ◽  
Rosario Osta
Keyword(s):  
Skeletal Muscle ◽  
Spinal Cord ◽  
Sex Differences ◽  
Sexual Dimorphism ◽  
Animal Models ◽  
Sex Bias ◽  
Wild Type ◽  
Male And Female ◽  
Physiological Conditions ◽  
Sequestosome 1

Sex bias has been described nowadays in biomedical research on animal models, although sexual dimorphism has been confirmed widely under pathological and physiological conditions. The main objective of our work was to study the sex differences in constitutive autophagy in spinal cord and skeletal muscle tissue from wild type mice. To examine the influence of sex on autophagy, mRNA and proteins were extracted from male and female mice tissues. The expressions of microtubule-associated protein 1 light chain 3 (LC3) and sequestosome 1 (p62), markers to monitor autophagy, were analyzed at 40, 60, 90, and 120 days of age. We found significant sex differences in the expression of LC3 and p62 in both tissues at these ages. The results indicated that sex and tissue specific differences exist in constitutive autophagy. These data underlined the need to include both sexes in the experimental groups to minimize any sex bias.

scholarly journals 2464 Sexual dimorphism in a mouse model of syndromic thoracic aortic aneurysm

2018 ◽  
Vol 2 (S1) ◽  
pp. 27-27
Author(s):  
Zheying Chen ◽  
Alan Daugherty ◽  
Mary Sheppard
Keyword(s):  
Extracellular Matrix ◽  
Sexual Dimorphism ◽  
Mouse Model ◽  
Aortic Aneurysms ◽  
Pcr Analysis ◽  
Wild Type ◽  
Aortic Dilation ◽  
Male And Female ◽  
Thoracic Aortic Aneurysms ◽  
Male Sex

OBJECTIVES/SPECIFIC AIMS: Pre-clinical and clinical observations have noted that increased aortic dilation is associated with male sex. Using an experimental model of severe, syndromic thoracic aortic aneurysms, we quantify aortic dilation and elastin stability in male Versus female mice. METHODS/STUDY POPULATION: Ascending aortas from male and female FBN1mgR/mgR mice and their wild type littermates were assessed every 4 weeks from 6 to 18 weeks of age by ultrasound. Measurements were taken luminal edge to luminal edge in diastole. At termination, aortas were harvested for RT-PCR analysis of extracellular matrix genes. Aortas were serially sectioned and elastin fragmentation was imaged by auto-fluorescence. RESULTS/ANTICIPATED RESULTS: At 12 weeks of age, differences of aortic diameters between male and female FBN1mgR/mgR mice were significantly different (2.24±0.43 vs. 1.57±0.22 mm; p=0.002), while there were no significant differences between sexes of wild type littermates (1.29±0.13 vs. 1.23±0.08 mm; p=0.71). Male sex was associated with increased elastin but not fibrillin-1 mRNA expression. Ascending aortas from male and female FBN1mgR/mgR mice significantly differed in the degree of elastin fragmentation (2.76 vs. 1.85 breaks/ 100 µm aorta; p=0.03). DISCUSSION/SIGNIFICANCE OF IMPACT: Sexual dimorphism of thoracic aortic dilation observed in human TAA patients was recapitulated in the fibirllin-1 hypomorphic mouse model of syndromic thoracic aortic aneurysms. Differences in this mouse model could be explained by the differential expression of extracellular matrix genes.

scholarly journals CBMT-45. SEX-SPECIFIC METABOLIC ADAPTIONS IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi42-vi43
Author(s):  
Jasmin Sponagel ◽  
Shanshan Zhang ◽  
Prakash Chinnaiyan ◽  
Joshua Rubin ◽  
Joseph Ippolito
Keyword(s):  
Sex Differences ◽  
Sexual Dimorphism ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Mitochondrial Activity ◽  
Male And Female ◽  
Glutamine Deprivation ◽  
Novel Treatment Strategies

Abstract Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. GBM occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that male patients exhibit a significantly higher abundance of TCA cycle metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Strikingly, sex differences in TCA cycle flux were entirely driven by glutamine flux, not glucose flux, suggesting a sex-specific role for glutamine in GBM. Metabolic manipulation through glutamine deprivation resulted in a greater growth inhibition in male GBM cells. Glutamine itself can be utilized for anabolic reactions or it can be converted to glutamate by glutaminase. Only male GBM cells were sensitive to pharmacological glutaminase inhibition with BPTES or CB-839, suggesting that male GBM cells are glutamate dependent while female GBM cells are not. Concordantly, we found significantly higher glutaminase levels in male GBM cells. Furthermore, we found that numerous metabolites (including NADH, ATP, and glutathione) involved in cellular processes downstream of glutamate were more abundant in male GBM cells. In contrast, female GBM cells were resistant to low glutamine conditions and glutaminase inhibitors unless glutamine-synthase activity was disrupted, suggesting that glutamine synthesis might play a more prominent role in female GBM. Together, these data indicate that male and female GBM differ in their metabolic adaptions. Male GBM utilize glutamate to fuel the TCA cycle and mitochondrial activity while female GBM synthesize and utilize glutamine itself. This sexual dimorphism in metabolic reprogramming reveals novel sex specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.

scholarly journals Sex Differences in Angiotensin II-Induced Hypertension and Kidney Injury: Role of AT1a Receptors in The Proximal Tubule of The Kidney

2021 ◽  
Author(s):  
Ana Paula Oliverio Leite ◽  
Xiao Chun Li ◽  
Ruman Hassan ◽  
Xiaowen Zheng ◽  
Barbara T Alexander ◽  
...  
Keyword(s):  
Sex Differences ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Wild Type ◽  
Male And Female ◽  
Induced Hypertension ◽  
Different Strains

In the present study, we tested the hypothesis that there are significant sex differences in angiotensin II (Ang II)-induced hypertension and kidney injury using male and female wild-type and proximal tubule-specific AT1a receptor knockout mice (PT-Agtr1a-/-). Twelve groups (n=8-12 per group) of adult male and female wild-type and PT-Agtr1a-/- mice were infused with a pressor dose of Ang II via osmotic pump for 2 weeks (1.5 mg/kg/day, i.p.) and simultaneously treated with or without losartan (20 mg/kg/day, p.o.) to determine the respective roles of AT1a receptors in the proximal tubules versus systemic tissues. Basal systolic, diastolic, and mean arterial pressure were approximately 13 ± 3 mmHg lower (P<0.01), while basal 24 h urinary Na+, K+, and Cl- excretion were significantly higher in both male and female PT-Agtr1a-/- mice than wild-type controls (P<0.01) without significant sex differences between different strains. Both male and female wild-type and PT-Agtr1a-/- mice developed hypertension (P<0.01), and the magnitudes of the pressor responses to Ang II were similar between male and female wild-type and PT-Agtr1a-/- mice (n.s.). Likewise, Ang II-induced hypertension was significantly attenuated in both male and female PT-Agtr1a-/- mice (P<0.01). Furthermore, losartan attenuated the hypertensive responses to Ang II to similar extents in both male and female wild-type and PT-Agtr1a-/- mice. Finally, Ang II-induced kidney injury was attenuated in PT-Agtr1a-/- mice (P<0.01). In conclusion, the present study demonstrates that deletion of AT1a receptors in the proximal tubules of the kidney attenuates Ang II-induced hypertension and kidney injury without revealing significant sex differences.

scholarly journals New Insights into Sexual Dimorphism during Progression of Heart Failure and Rhythm Disorders

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1837-1845 ◽  
Author(s):  
Jérôme Thireau ◽  
Franck Aimond ◽  
Denise Poisson ◽  
BeiLi Zhang ◽  
Patrick Bruneval ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sexual Dimorphism ◽  
Gonadal Hormones ◽  
Left Ventricular ◽  
Conduction Time ◽  
Wild Type ◽  
Mice Model ◽  
Patch Clamp Technique ◽  
Male And Female ◽  
Intraventricular Conduction

Neurohormonal imbalance is a key determinant of the progression of heart failure (HF), which results in an elevated risk of mortality. A better understanding of mechanisms involved may influence treatment strategies. The incidence and prevalence of HF are lower in women. We explored sexual dimorphism in the progression of HF using a mice model of neurohormonal-dependent HF. Male and female mice overexpressing the human β2-adrenergic receptor (TG4 strain) develop HF. We compared TG4 animals with age-matched wild-type controls. Cardiac function was studied in vivo by echocardiography and electrocardiography. Histological studies were performed. Conduction parameters were assessed by intracardiac electrophysiological exploration, as was the occurrence of spontaneous and inducible arrhythmias. The patch-clamp technique was used to determine the cellular electrophysiological profile. The role of hormonal status in HF progression was investigated by surgical gonadectomy. High mortality rate was observed in TG4 mice with a dramatic difference between males and females. Male TG4 mice exhibited intraventricular conduction abnormalities, as measured by infrahisian interval and QRS durations potentially determining reentrant circuits and increasing susceptibility to arrhythmia. The severity of HF was correlated with the degree of fibrosis, which was modulated by the gonadal hormones. Action potentials recorded from male and female left ventricular cardiomyocytes were indistinguishable, although both sexes exhibited delayed repolarization when compared with their wild-type counterparts. In conclusion, female TG4 mice were better protected than males against cardiac remodeling and rhythm disorders. A link between fibrosis, conduction time, and mortality was established in relation with sex hormones.

scholarly journals Sex Differences in a Rat Model of Peripheral Neuropathic Pain and Associated Levels of Endogenous Cannabinoid Ligands

2021 ◽  
Vol 2 ◽  
Author(s):  
Laura Boullon ◽  
David P. Finn ◽  
Álvaro Llorente-Berzal
Keyword(s):  
Sex Differences ◽  
Neuropathic Pain ◽  
Sexual Dimorphism ◽  
Female Rats ◽  
Male Rats ◽  
World Population ◽  
Chronic Neuropathic Pain ◽  
Peripheral Neuropathic Pain ◽  
Male And Female ◽  
Endogenous Cannabinoid

Chronic neuropathic pain is a major unmet clinical need affecting 10% of the world population, the majority of whom suffer from co-morbid mood disorders. Sex differences have been reported in pain prevalence, perception and response to analgesics. However, sexual dimorphism in chronic neuropathic pain and the associated neurobiology, are still poorly understood. The lack of efficacy and the adverse effects associated with current pharmacological treatments, further underline the need for new therapeutic targets. The endocannabinoid system (ECS) is a lipid signalling system which regulates a large number of physiological processes, including pain. The aim of this study was to investigate sexual dimorphism in pain-, anxiety- and depression-related behaviours, and concomitant alterations in supraspinal and spinal endocannabinoid levels in the spared nerve injury (SNI) animal model of peripheral neuropathic pain. Sham or SNI surgery was performed in adult male and female Sprague-Dawley rats. Mechanical and cold allodynia was tested weekly using von Frey and acetone drop tests, respectively. Development of depression-related behaviours was analysed using sucrose splash and sucrose preference tests. Locomotor activity and anxiety-related behaviours were assessed with open field and elevated plus maze tests. Levels of endocannabinoid ligands and related N-acylethanolamines in supraspinal regions of the descending inhibitory pain pathway, and spinal cord, were analysed 42 days post-surgery. SNI surgery induced allodynia in rats of both sexes. Female-SNI rats exhibited earlier onset and greater sensitivity to cold and mechanical allodynia than their male counterparts. In male rats, SNI induced a significant reduction of rearing, compared to sham controls. Trends for depressive-like behaviours in females and for anxiety-like behaviours in males were observed after SNI surgery but did not reach statistical significance. No concomitant alterations in levels of endogenous cannabinoid ligands and related N-acylethanolamines were observed in the regions analysed. Our results demonstrate differential development of SNI-induced nociceptive behaviour between male and female rats suggesting important sexually dimorphic modifications in pain pathways. SNI had no effect on depression- or anxiety-related behaviours in animals of either sex, or on levels of endocannabinoid ligands and related N-acylethanolamines across the regions involved in the descending modulation of nociception at the time points investigated.

Ca2+ influx through α1S DHPR may play a role in regulating Ca2+ release from RyR1 in skeletal muscle

2004 ◽  
Vol 286 (1) ◽  
pp. C73-C78 ◽  
Author(s):  
Alexander Shtifman ◽  
Cecilia Paolini ◽  
José R. López ◽  
Paul D. Allen ◽  
Feliciano Protasi
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Bathing Solution ◽  
Wild Type ◽  
Release Channel ◽  
Mechanical Coupling ◽  
Physiological Conditions ◽  
Dihydropyridine Receptors

Differentiated primary myotubes isolated from wild-type mice exhibit ryanodine-sensitive, spontaneous global Ca2+ oscillations as well as spontaneous depolarizations in the plasma membrane. Immunolabeling of these myotubes showed expression of both α1S dihydropyridine receptors (DHPRs) and ryanodine-sensitive Ca2+-release channel 1 (RyR1), the two key proteins in skeletal excitation-contraction (E-C) coupling. Spontaneous global Ca2+ oscillations could be inhibited by addition of 0.1 mM CdCl2/0.5 mM LaCl3 or 5 μM nifedipine to the extracellular bathing solution. After either treatment, Ca2+ oscillations could be restored upon extensive washing. Although exposure to DHPR antagonists completely blocked Ca2+ oscillations, normal orthograde signaling between DHPRs and RyRs, such as that elicited by 80 mM KCl depolarization, was still observed. In addition, we showed that spontaneous Ca2+ oscillations were never present in cultured mdg myotubes, which lack the expression of α1SDHPRs. These results suggest that under physiological conditions in conjunction with the mechanical coupling between the α1SDHPRs and RyR1, the initiation of Ca2+ oscillations in myotubes may be facilitated, in part, by the Ca2+ influx through the α1s-subunit of the DHPR.

scholarly journals Sexual Dimorphism in Doxorubicin-induced Systemic Inflammation: Implications for Hepatic Cytochrome P450 Regulation

2020 ◽  
Vol 21 (4) ◽  
pp. 1279
Author(s):  
Marianne K.O. Grant ◽  
Ibrahim Y. Abdelgawad ◽  
Christine A. Lewis ◽  
Beshay N. Zordoky
Keyword(s):  
Sex Differences ◽  
Cytochrome P450 ◽  
Sexual Dimorphism ◽  
Inflammatory Response ◽  
Systemic Inflammation ◽  
Dependent Manner ◽  
Male And Female ◽  
Female Mice ◽  
Organ Toxicity ◽  
Hepatic Cytochrome

Doxorubicin (DOX) is an effective chemotherapeutic agent used to treat a wide variety of malignancies. In addition to its multi-organ toxicity, DOX treatment has been shown to induce systemic inflammation in patients and experimental animals. Inflammation alters the expression of hepatic cytochrome P450 (CYP) enzymes, which play important roles in drug metabolism and DOX-induced toxicity. Significant sex differences have been reported in DOX-induced toxicity; however, sex differences in DOX-induced systemic inflammation and the potential effects on hepatic CYP expression have not been determined. In the current work, male and female C57Bl/6 mice were administered DOX (20 mg/kg by intraperitoneal injection), and groups of mice were sacrificed 24 and 72 h after DOX administration. DOX elicited a systemic inflammatory response in both male and female mice, but the inflammatory response was stronger in male mice. DOX altered the expression of hepatic CYP isoforms in a sex-dependent manner. Most notably, inhibition of Cyp2c29 and Cyp2e1 was stronger in male than in female mice, which paralleled the sex differences in systemic inflammation. Therefore, sex differences in DOX-induced systemic inflammation may lead to sexually dimorphic drug interactions, in addition to contributing to the previously reported sexual dimorphism in specific DOX-induced organ toxicity.

scholarly journals Microvascular Sex- and Age- Dependent Phosphodiesterase Expression

2021 ◽  
Vol 2 ◽  
Author(s):  
Jianjie Wang ◽  
Murtaza M. Kazmi ◽  
Virginia H. Huxley
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Sexual Dimorphism ◽  
Cyclic Nucleotide ◽  
Female Rats ◽  
Adult Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Age Dependent ◽  
Camp And Cgmp

Objective: The cyclic nucleotide second messengers, cAMP and cGMP, are pivotal regulators of vascular functions; their cellular levels are tightly controlled by the cyclic nucleotide hydrolases, phosphodiesterases (PDE). Biologic sex and age are recognized as independent factors impacting the mechanisms mediating both vascular health and dysfunction. This study focused on microvessels isolated from male and female rats before (juvenile) and after (adult) sexual maturity under resting conditions. We tested the hypothesis that sexual dimorphism in microvascular PDE expression would be absent in juvenile rats, but would manifest in adult rats.Methods: Abdominal skeletal muscle arterioles and venules were isolated from age-matched juvenile and adult male and female rats under resting conditions. Transcripts of five PDE families (1–5) associated with coronary and vascular function with a total of ten genes were measured using TaqMan real-time RT-PCR and protein expression of microvessel PDE4 was assessed using immunoblotting and immunofluorescence.Results: Overall expression levels of PDE5A were highest while PDE3 levels were lowest among the five PDE families (p < 0.05) regardless of age or sex. Contrary to our hypothesis, in juveniles, sexual dimorphism in PDE expression was observed in three genes: arterioles (PDE1A, female > male) and venules (PDE1B and 3A, male > female). In adults, gene expression levels in males were higher than females for five genes in arterioles (PDE1C, 3A, 3B, 4B, 5A) and three genes (PDE3A, 3B, and 5A) in venules. Furthermore, age-related differences were observed in PDE1-5 (in males, adult > juvenile for most genes in arterioles; in females, adult > juvenile for arteriolar PDE3A; juvenile gene expression > adult for two genes in arterioles and three genes in venules). Immunoblotting and immunofluorescence analysis revealed protein expression of microvessel PDE4.Conclusion: This study revealed sexual dimorphism in both juvenile and adult rats, which is inconsistent with our hypothesis. The sex- and age-dependent differences in PDE expression implicate different modulations of cAMP and cGMP pathways for microvessels in health. The implication of these sex- and age-dependent differences, as well as the duration and microdomain of PDE1-5 activities in skeletal muscle microvessels, in both health and disease, require further investigation.

scholarly journals Sex differences in mitochondrial Ca2+ handling in mouse fast-twitch skeletal muscle in vivo

2020 ◽  
Vol 128 (2) ◽  
pp. 241-251 ◽  
Author(s):  
Daiki Watanabe ◽  
Koji Hatakeyama ◽  
Ryo Ikegami ◽  
Hiroaki Eshima ◽  
Kazuyoshi Yagishita ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sex Differences ◽  
Cyclopiazonic Acid ◽  
Atpase Inhibitor ◽  
Fiber Volume ◽  
Male And Female ◽  
Significant Difference ◽  
Mitochondrial Volume ◽  
Fast Twitch

We investigated sex differences in mitochondrial Ca2+ handling properties in mouse fast-twitch skeletal muscle. Changes in cytoplasmic Ca2+ concentration ([Ca2+]cyto) were measured in vivo using tibialis anterior muscles from male and female mice. The muscles were exposed to increasing concentrations of cyclopiazonic acid [CPA; sarcoplasmic reticulum (SR) Ca2+-ATPase inhibitor] (from 10 to 30 to 50 μM at 10 min intervals). Thirty minutes after treatment, [Ca2+]cyto was increased by 31.6 ± 2.0% and 13.5 ± 4.5% of initial [Ca2+]cyto in male and female muscles, respectively, and there was a significant difference between sexes. However, muscle preincubation for 5 min with 10 μM carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (an inhibitor of mitochondria Ca2+ uptake) eradicated this difference between sexes with respect to the CPA-induced [Ca2+]cyto increase. Both intermyofibrillar mitochondrial number and volume, assessed in longitudinal fiber sections, were higher in females compared with males (mitochondria number: 13.1 ± 1.0 in males vs. 19.9 ± 2.3 in females; mitochondrial volume: 0.034 ± 0.004 μm3/μm3 fiber volume in males vs. 0.066 ± 0.008 μm3/μm3 fiber volume in females, both P < 0.05). There were no sex differences in the content of SR Ca2+-ATPase, mitochondrial Ca2+ uniporter, mitofusin (Mfn) 1, or Mfn2. These results suggest that 1) mitochondrial Ca2+ uptake ability is greater in female than male myocytes, and 2) this superior Ca2+ uptake ability of female myocytes is due, partly, to the higher intermyofibrillar mitochondrial content but not to the expression of mitochondrial proteins related to mitochondrial Ca2+ uptake. NEW & NOTEWORTHY This investigation presents evidence that female versus male fast-twitch muscle exhibits a greater mitochondrial calcium ion uptake capability that is partly conferred by the higher intermyofibrillar mitochondrial volume density.

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