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Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities.

ABSTRACT: In chronic obstructive pulmonary disease (COPD), lower limb dysfunction is associated with reduced exercise capacity, increased hospitalizations and mortality. We investigated sex differences in the prevalence of quadriceps dysfunction and fibre abnormalities in a large COPD cohort, controlling for the normal sex differences in health. We compared existing data from 76 male and 38 female COPD patients where each variable was expressed as a function of gender-specific normal values (obtained from 16 male and 14 female controls). Female COPD patients had lower quadriceps muscle strength and peak workload on a maximal incremental cycle ergometry protocol compared to male patients. Female patients had a smaller type II fibre cross-sectional area (CSA) compared to male patients, suggesting a greater female preponderance to fibre atrophy, although this result was largely driven by a few male patients with a large type II fibre CSA. Female patients had significantly higher concentrations of a number of plasma pro-inflammatory cytokines including tumour necrosis factor alpha and interleukin 8 (IL8), but not lower levels of physical activity or arterial oxygenation, compared to males. Our data confirm results from a previous small study and suggest that female COPD patients have a greater prevalence of muscle wasting and weakness. Larger studies investigating sex differences in COPD-related muscle atrophy and weakness are needed, as the results will have implications for monitoring in clinical practice and for design of clinical trials evaluating novel muscle anabolic agents.

SUBMITTER: Sharanya A

PROVIDER: S-EPMC6537500 | biostudies-literature | 2019 Jan-Dec

REPOSITORIES: biostudies-literature

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Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities.

Sharanya Adithya A Ciano Margherita M Withana Shirmila S Kemp Paul Richard PR Polkey Michael Iain MI Sathyapala Samantha Amanda SA

Chronic respiratory disease 20190101

In chronic obstructive pulmonary disease (COPD), lower limb dysfunction is associated with reduced exercise capacity, increased hospitalizations and mortality. We investigated sex differences in the prevalence of quadriceps dysfunction and fibre abnormalities in a large COPD cohort, controlling for the normal sex differences in health. We compared existing data from 76 male and 38 female COPD patients where each variable was expressed as a function of gender-specific normal values (obtained from ...[more]

PMID: 31131626

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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.

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.

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.

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.

Dataset Information

Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities.

Publications

Sex differences in COPD-related quadriceps muscle dysfunction and fibre abnormalities.

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