Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities.
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ABSTRACT:
SUBMITTER: Sharanya A
PROVIDER: S-EPMC6537500 | biostudies-literature | 2019 Jan-Dec
REPOSITORIES: biostudies-literature
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Project description:IntroductionExercise is an important countermeasure to limb muscle dysfunction in COPD. The two major training modalities in COPD rehabilitation, endurance training (ET) and resistance training (RT), may both be efficient in improving muscle strength, exercise capacity, and health-related quality of life, but the effects on quadriceps muscle characteristics have not been thoroughly described.MethodsThirty COPD patients (forced expiratory volume in 1 second: 56% of predicted, standard deviation [SD] 14) were randomized to 8 weeks of ET or RT. Vastus lateralis muscle biopsies were obtained before and after the training intervention to assess muscle morphology and metabolic and angiogenic factors. Symptom burden, exercise capacity (6-minute walking and cycle ergometer tests), and vascular function were also assessed.ResultsBoth training modalities improved symptom burden and exercise capacity with no difference between the two groups. The mean (SD) proportion of glycolytic type IIa muscle fibers was reduced after ET (from 48% [SD 11] to 42% [SD 10], P<0.05), whereas there was no significant change in muscle fiber distribution with RT. There was no effect of either training modality on muscle capillarization, angiogenic factors, or vascular function. After ET the muscle protein content of phosphofructokinase was reduced (P<0.05) and the citrate synthase content tended increase (P=0.08) but no change was observed after RT.ConclusionAlthough both ET and RT improve symptoms and exercise capacity, ET induces a more oxidative quadriceps muscle phenotype, counteracting muscle dysfunction in COPD.
| S-EPMC5087783 | biostudies-literature
Project description:There is sexual dimorphism of skeletal muscle, the most obvious feature being the larger muscle mass of men. The molecular basis for this difference has not been clearly defined. To identify genes that might contribute to the relatively greater muscularity of men, we compared skeletal muscle gene expression profiles of 15 normal men and 15 normal women by using comprehensive oligonucleotide microarrays. Although there were sex-related differences in expression of several hundred genes, very few of the differentially expressed genes have functions that are obvious candidates for explaining the larger muscle mass of men. The men tended to have higher expression of genes encoding mitochondrial proteins, ribosomal proteins, and a few translation initiation factors. The women had >2-fold greater expression than the men (P<0.0001) of two genes that encode proteins in growth factor pathways known to be important in regulating muscle mass: growth factor receptor-bound 10 (GRB10) and activin A receptor IIB (ACVR2B). GRB10 encodes a protein that inhibits insulin-like growth factor-1 (IGF-1) signaling. ACVR2B encodes a myostatin receptor. Quantitative RT-PCR confirmed higher expression of GRB10 and ACVR2B genes in these women. In an independent microarray study of 10 men and 9 women with facioscapulohumeral dystrophy, women had higher expression of GRB10 (2.7-fold, P<0.001) and ACVR2B (1.7-fold, P<0.03). If these sex-related differences in mRNA expression lead to reduced IGF-1 activity and increased myostatin activity, they could contribute to the sex difference in muscle size.
| S-EPMC2148100 | biostudies-literature
Project description: Not available
| S-EPMC3039204 | biostudies-literature
Project description:BACKGROUND:Female smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. Tertiary lymphoid follicles are often found in the lungs of patients with severe COPD but sex-related differences have not been previously investigated. We determined the impact of female sex hormones on chronic cigarette smoke-induced expression of lymphoid aggregates in mice with COPD-like pathologies. METHODS:Lymphoid aggregate counts, total aggregate cross-sectional area and foamy macrophage counts were determined morphometrically in male, female, and ovariectomized mice exposed to air or cigarette smoke for 6?months. B-cell activating factor (BAFF) protein expression and markers of oxidative stress were evaluated in mouse lung tissues by immunofluorescence staining and gene expression analyses. Quantitative histology was performed on lung tissue sections of human COPD lungs to evaluate follicle formation. RESULTS:Lymphoid follicle and foamy macrophage counts as well as the total follicle cross-sectional area were differentially increased in lung tissues of female mice compared to male mice, and these differences were abolished by ovariectomy. These lymphoid aggregates were positive for CD45, CD20, CD21 and BAFF expression. Differential increases in Mmp12 and Cxcl2 gene expression correlated with an increase in foamy macrophages in parenchymal tissues of female but not male mice after smoke exposure. Parenchymal tissues from female mice failed to induce antioxidant-related genes in response to smoke exposure, and this effect was restored by ovariectomy. 3-nitrotyrosine, a stable marker of oxidative stress, positively correlated with Mmp12 and Cxcl2 gene expression. Hydrogen peroxide induced BAFF protein in mouse macrophage cell line. In human lung tissues, female smokers with severe COPD demonstrated increased numbers of lymphoid follicles compared with males. CONCLUSIONS:Chronic smoke exposure increases the risk of lymphoid aggregate formation in female mice compared with male mice, which is mediated female sex hormones and BAFF expression in an oxidative environment.
| S-EPMC7006095 | biostudies-literature
Project description:AimTo uncover sex-related microvascular abnormalities that underlie the early presentation of reduced perfusion in leg skeletal muscle in a type II rat model of diabetic cardiomyopathy.Methods and resultsDiabetes was induced using a non-obese, diet-based, low-dose streptozotocin model in adult female (18 diabetic, 9 control) and male rats (29 diabetic, 11 control). Time-course monitoring over 12 months following diabetes induction was performed using echocardiography, treadmill exercise, photoacoustic imaging, flow-mediated dilation (FMD), histopathology, and immunohistochemistry. Diabetic rats maintained normal weights. Hypertension appeared late in both diabetic males (7 months) and females (10 months), while only diabetic males had elevated cholesterol (7 months). On echocardiography, all diabetic animals maintained normal ejection fraction and exhibited diastolic dysfunction, mild systolic dysfunction, and a slightly enlarged left ventricle. Exercise tolerance declined progressively and early in males (4 months), later in females (8 months); FMD showed lower baseline femoral arterial flow but unchanged reactivity in both sexes (5 months); and photoacoustic imaging showed lower tissue oxygen saturation in the legs of diabetic males (4 months) and diabetic females (10 months). Myocardial perfusion was normal in both sexes. Histopathology at the final timepoint of Month 10 (males) and Month 12 (females) revealed that myocardial microvasculature was normal in both vessel density and structure, thus explaining normal perfusion on imaging. However, leg muscle microvasculature exhibited perivascular smooth muscle thickening around small arterioles in diabetic females and around large arterioles in diabetic males, explaining the depressed readings on photoacoustic and FMD. Histology also confirmed the absence of commonly reported HFpEF markers, including microvessel rarefaction, myocardial fibrosis, and left ventricular hypertrophy.ConclusionExercise intolerance manifesting early in the progression of diabetic cardiomyopathy can be attributed to decreased perfusion to the leg skeletal muscle due to perivascular smooth muscle thickening around small arterioles in females and large arterioles in males. This microvascular abnormality was absent in the myocardium, where perfusion levels remained normal throughout the study. We conclude that although skeletal muscle microvascular dysfunction of the vasculature presents at different levels depending on sex, it consistently presents early in both sexes prior to overt cardiac changes such as rarefaction, fibrosis, or hypertrophy.
| S-EPMC9157579 | biostudies-literature
Project description:Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA methylation; however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle samples (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR < 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci; however, these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen (AR), estrogen (ESR1), and glucocorticoid (NR3C1) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR < 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p value = 4.6e-13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes (FOXO3A, ALDH1A1, and GGT7) in the Gene SMART cohort with qPCR. GGT7, involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.
| S-EPMC8567658 | biostudies-literature
Project description:Individualized outcome prediction classifiers were successfully constructed through expression profiling of a total of 779 genes in microglial cells from 36 mice, which had been consecutively operated on within a defined short period of time
2022-05-20 | GSE203202 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a "two-hit" mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.
| S-EPMC9253085 | biostudies-literature
Project description:ContextMultiple factors contribute to sexual dysfunction in men with obesity. Sex hormone levels are commonly abnormal in men with obesity and this abnormality is often the focus of management in clinical practice. The role of small fibre neuropathy in obesity-related sexual dysfunction is not well established.ObjectiveWe aimed to investigate the relationship between sexual function, sex hormone levels and small nerve fibre morphology in men with severe obesity.Materials and methodsA prospective study of 29 men with severe obesity was undertaken. Sexual function was assessed using the European Male Ageing Study Sexual Function Questionnaire. Small nerve fibre morphology was quantified using corneal confocal microscopy. Sex hormone levels were measured by mass spectrophotometry.ResultsErectile dysfunction was present in 72% of the cohort with a higher prevalence of diabetes among the symptomatic group (88% vs 38%, p = 0.006). Corneal nerve fibre length (CNFL) and corneal nerve fibre density (CNFD) were both significantly lower in participants with erectile dysfunction compared to those without (p = 0.039 and p = 0.048 respectively). The erectile function score correlated with CNFL (r = -0.418, p = 0.034) and CNFD (r = -0.411, p = 0.037). Total testosterone and calculated free testosterone levels did not differ significantly between men with or without erectile dysfunction (median 8.8 nmol/L vs 9.0 nmol/L, p = 0.914; and median 176 pmol/L vs 179 pmol/L, p = 0.351 respectively), infrequent sexual thoughts (median 8.1 nmol/L vs 9.2 nmol/L, p = 0.650; and median 184 pmol/L, vs 176 pmol/L, p = 0.619 respectively) and decreased morning erections (median 9.0 nmol/L vs 8.8 nmol/L, p = 0.655; and median 170 pmol/L vs 193 pmol/L, p = 0.278 respectively).ConclusionSexual dysfunction is highly prevalent in men with severe obesity. We found an association between small fibre neuropathy with erectile dysfunction with presence of diabetes a likely a significant contributing factor. We found no associations between testosterone levels with sexual symptoms (including frequency of sexual thoughts). The influence of small nerve fibre neuropathy on response to therapeutic interventions and whether interventions that improve small fibre neuropathy can improve erectile function in this population merits further study.
| S-EPMC6738611 | biostudies-literature
Project description:Quadriceps muscle weakness is an important component of chronic obstructive pulmonary disease (COPD). We hypothesised that quadriceps weakness would also be a feature of restrictive lung disease due to scoliosis. We studied 10 patients with severe scoliosis (median (interquartile range (IQR)) forced expiratory volume in 1 s (FEV(1))() 35.3 (11)% predicted), 10 patients with severe COPD (FEV(1) 26.5 (9.0)% pred) and 10 healthy age-matched adults. We measured quadriceps strength, exercise capacity and analysed quadriceps muscle biopsies for myosin heavy-chain (MyHC) isoform expression and the presence of oxidative stress. Both groups exhibited quadriceps weakness with median (IQR) maximal voluntary contraction force being 46.0 (17.0) kg, 21.5 (21.0) kg and 31.5 (11.0) kg, respectively (p = 0.02 and 0.04, respectively, for each patient group against controls). Oxidative stress was significantly greater in the quadriceps of both restrictive and COPD patients. The scoliosis patients exhibited a decrease in the proportion of MyHC type I compared with controls; median (IQR) 35.3 (18.5)% compared with 47.7 (9.3)%, p = 0.028. The scoliosis patients also showed an increase in MyHC IIx (26.3 (15.5)% compared with 11.3 (13.0)%, p = 0.01. Quadriceps weakness is a feature of severe scoliosis; the similarities between patients with scoliosis and patients with COPD suggest a common aetiology to quadriceps weakness in both conditions.
| S-EPMC3073323 | biostudies-literature