175 research outputs found
Molecular studies of exercise, skeletal muscle, and ageing [version 1; referees: 2 approved]
Get PDFThe purpose of an F1000 review is to reflect on the bigger picture, exploring controversies and new concepts as well as providing opinion as to what is limiting progress in a particular field. We reviewed about 200 titles published in 2015 that included reference to ‘skeletal muscle, exercise, and ageing’ with the aim of identifying key articles that help progress our understanding or research capacity while identifying methodological issues which represent, in our opinion, major barriers to progress. Loss of neuromuscular function with chronological age impacts on both health and quality of life. We prioritised articles that studied human skeletal muscle within the context of age or exercise and identified new molecular observations that may explain how muscle responds to exercise or age. An important aspect of this short review is perspective: providing a view on the likely ‘size effect’ of a potential mechanism on physiological capacity or ageing
Multiple sources of bias confound functional enrichment analysis of global -omics data
Get PDFSerious and underappreciated sources of bias mean that extreme caution should be applied when using or interpreting functional enrichment analysis to validate findings from global RNA- or protein-expression analyses
Device-measured Desk-based Occupational Sitting Patterns and Stress (hair cortisol and perceived stress)
Get PDFBackground: Stress and poor mental health are significant issues in the workplace and are a major cause of absenteeism and reduce productivity. Understanding what might contribute towards employee stress is important for managing mental health in this setting. Physical activity has been shown to be beneficial to stress but less research has addressed the potential negative impact of sedentary behaviour such as sitting. Therefore, the aim of this study was to assess the relationship between device-measured occupational desk-based sitting patterns and stress (hair cortisol levels (HCL), as a marker of chronic stress and self-reported perceived stress (PS)). Methods: Employees were recruited from four workplaces located in Central Scotland with large numbers of desk-based occupations. Seventy-seven participants provided desk-based sitting pattern data (desk-based sitting time/day and desk-based sit-to-stand transitions/day), a hair sample and self-reported perceived stress. HCL were measured using enzyme-linked immunosorbent assay and PS using the Cohen Self-Perceived Stress Scale. Linear regression models were used to test associations between desk-based sitting time/day, desk-based sit-to-stand transitions/day, HCL and PS. Results: There were no associations between any of the desk-based sitting measures and either HCL or PS. Conclusion. Desk-based sitting patterns in the workplace may not be related to stress when using HCL as a biomarker or PS. The relationship between sitting patterns and stress therefore requires further investigation
Adipose depot gene expression identifies intelectin-1 as potential mediator of the metabolic response to cancer and cachexia
Get PDFBackground Cancer cachexia is a poorly understood metabolic consequence of cancer. During cachexia, different adipose depots demonstrate differential wasting rates. Animal models suggest adipose tissue may be a key driver of muscle wasting through fat–muscle crosstalk, but human studies in this area are lacking. We performed global gene expression profiling of visceral (VAT) and subcutaneous (SAT) adipose from weight stable and cachectic cancer patients and healthy controls. Methods Cachexia was defined as >2% weight loss plus low computed tomography‐muscularity. Biopsies of SAT and VAT were taken from patients undergoing resection for oesophago‐gastric cancer, and healthy controls (n = 16 and 8 respectively). RNA was isolated and reverse transcribed. cDNA was hybridised to the Affymetrix Clariom S microarray and data analysed using R/Bioconductor. Differential expression of genes was assessed using empirical Bayes and moderated‐t‐statistic approaches. Category enrichment analysis was used with a tissue‐specific background to examine the biological context of differentially expressed genes. Selected differentially regulated genes were validated by qPCR. Enzyme‐linked immunosorbent assay (ELISA) for intelectin‐1 was performed on all VAT samples. The previously‐described cohort plus 12 additional patients from each group also had plasma I = intelectin‐1 ELISA carried out. Results In VAT vs. SAT comparisons, there were 2101, 1722, and 1659 significantly regulated genes in the cachectic, weight stable, and control groups, respectively. There were 2200 significantly regulated genes from VAT in cachectic patients compared with controls. Genes involving inflammation were enriched in cancer and control VAT vs. SAT, although different genes contributed to enrichment in each group. Energy metabolism, fat browning (e.g. uncoupling protein 1), and adipogenesis genes were down‐regulated in cancer VAT (P = 0.043, P = 5.4 × 10−6 and P = 1 × 10−6 respectively). The gene showing the largest difference in expression was ITLN1, the gene that encodes for intelectin‐1 (false discovery rate‐corrected P = 0.0001), a novel adipocytokine associated with weight loss in other contexts. Conclusions SAT and VAT have unique gene expression signatures in cancer and cachexia. VAT is metabolically active in cancer, and intelectin‐1 may be a target for therapeutic manipulation. VAT may play a fundamental role in cachexia, but the down‐regulation of energy metabolism genes implies a limited role for fat browning in cachectic patients, in contrast to pre‐clinical models
A systematic review and Bayesian meta-analysis assessing intelectin-1 in cancer patients and healthy individuals
Get PDFBackground: Intelectin-1 (ITLN1) is an adipokine with multiple physiological functions, including a role in tumour formation and development. Previous research reported variable ITLN1 levels for cancer patients and healthy individuals. This study aimed to compare ITLN1 concentrations between controls and cancer patients and to determine the adipokine’s physiological level. Methods: Five databases were searched in January 2022 for studies that measured the level of ITLN1 in adults that were healthy or diagnosed with any type of cancer. After title, abstract and full-text screening, the methodological quality of the studies was assessed. The extracted data were meta-analysed using the R language and Bayesian statistical techniques. Results: Overall, 15 studies compared circulating ITLN1 levels between healthy individuals (n=3424) and cancer patients (n=1538), but no differences were observed between these studies. ITLN1 was not different between groups in an analysis that evaluated high-quality studies only (n=5). The meta-analysis indicated considerably higher ITLN1 levels in gastrointestinal (i.e., colorectal, pancreatic, gastric) cancer compared to controls, while the other cancer types did not demonstrate differences between groups. The mean ITLN1 level of healthy individuals was 234 ± 21ng/ml (n=136), while the average value in high-quality studies (n=52) was 257 ± 31ng/ml. Conclusion: Different types of cancer showed different circulating ITLN1 patterns. Circulating ITLN1 concentration was higher in gastrointestinal cancer compared to controls, with strong support from the meta-analytical model. Our analysis also determined the mean ITLN1 level in healthy individuals; this is a crucial starting point for understanding how this cytokine associates with diseases. Two-thirds of the studies were of low methodological quality and thus, future work in this field must focus on improved methods. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=303406, identifier CRD42022303406
Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes
Get PDFSkeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers. We profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes. The muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 × 10-8), post-translational modification (P < 9.7 × 10-5) and developmental (P < 1.3 × 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation. We provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions
Variation in the Early Host-Pathogen Interaction of Bovine Macrophages with Divergent Mycobacterium bovis Strains in the United Kingdom
Get PDFPublication history: Accepted - 8 December 2017; Published online - 20 December 2017.Bovine tuberculosis has been an escalating animal health issue in the
United Kingdom since the 1980s, even though control policies have been in place
for over 60 years. The importance of the genetics of the etiological agent, Mycobacterium bovis, in the reemergence of the disease has been largely overlooked. We
compared the interaction between bovine monocyte-derived macrophages (bMDM)
and two M. bovis strains, AF2122/97 and G18, representing distinct genotypes currently circulating in the United Kingdom. These M. bovis strains exhibited differences
in survival and growth in bMDM. Although uptake was similar, the number of viable
intracellular AF2122/97 organisms increased rapidly, while G18 growth was constrained for the first 24 h. AF2122/97 infection induced a greater transcriptional response by bMDM than G18 infection with respect to the number of differentially expressed genes and the fold changes measured. AF2122/97 infection induced more
bMDM cell death, with characteristics of necrosis and apoptosis, more inflammasome
activation, and a greater type I interferon response than G18. In conclusion, the two
investigated M. bovis strains interact in significantly different ways with the host
macrophage. In contrast to the relatively silent infection by G18, AF2122/97 induces
greater signaling to attract other immune cells and induces host cell death, which
may promote secondary infections of naive macrophages. These differences may affect early events in the host-pathogen interaction, including granuloma development, which could in turn alter the progression of the disease. Therefore, the potential involvement of M. bovis genotypes in the reemergence of bovine tuberculosis in
the United Kingdom warrants further investigation.Recombinant TNF and IL-10 were provided under the auspices of the Biotechnology and Biological Sciences Research Council (BBSRC) grants (BB/I019863/1 and BB/I020519/1) with the support of the Scottish Government as an Industrial Partnership Award with AbD Serotec (a Bio-Rad Company).
This work was supported by the European Framework 7 small collaborative project MACROSYS (FP7-KBBE-2007-1-1-2). E.J.G. was also supported by a BBSRC Strategic Programme grant (Control of Infectious Diseases [BB/P013740/1]
Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation
Get PDFThe goal of the current work was to profile positive (mTORC1 activation, autocrine/paracrine growth factors) and negative [AMPK, unfolded protein response (UPR)] pathways that might regulate overload-induced mTORC1 (mTOR complex 1) activation with the hypothesis that a number of negative regulators of mTORC1 will be engaged during a supraphysiological model of hypertrophy. To achieve this, mTORC1- IRS-1/2 signaling, BiP/CHOP/IRE1, and AMPK activation were determined in rat plantaris muscle following synergist ablation (SA). SA resulted in significant increases in muscle mass of 4% per day throughout the 21 days of the experiment. The expression of the insulin-like growth factors (IGF) were high throughout the 21st day of overload. However, IGF signaling was limited, since IRS-1 and -2 were undetectable in the overloaded muscle from day 3 to day 9. The decreases in IRS-1/2 protein were paralleled by increases in GRB10 Ser501/503 and S6K1 Thr389 phosphorylation, two mTORC1 targets that can destabilize IRS proteins. PKB Ser473 phosphorylation was higher from 3– 6 days, and this was associated with increased TSC2 Thr939 phosphorylation. The phosphorylation of TSC2 Thr1345 (an AMPK site) was also elevated, whereas phosphorylation at the other PKB site, Thr1462, was unchanged at 6 days. In agreement with the phosphorylation of Thr1345, SA led to activation of AMPK1 during the initial growth phase, lasting the first 9 days before returning to baseline by day 12. The UPR markers CHOP and BiP were elevated over the first 12 days following ablation, whereas IRE1 levels decreased. These data suggest that during supraphysiological muscle loading at least three potential molecular brakes engage to downregulate mTORC1. m
Relationship between insulin sensitivity and menstrual cycle is modified by BMI, fitness, and physical activity in NHANES
Get PDFContext There is evidence demonstrating variation in insulin sensitivity across the menstrual cycle. However, to date, research has yielded inconsistent results. Objective This study investigated variation in insulin sensitivity across the menstrual cycle and associations with BMI, physical activity and cardiorespiratory fitness. Design Data from 1906 premenopausal women in NHANES cycles 1999-2006 were analysed. Main outcome measures Menstrual cycle day was assessed using questionnaire responses recording days since last period. Rhythmic variation of plasma glucose, triglyceride and insulin, homeostatic model of insulin resistance (HOMA-IR) and adipose tissue insulin resistance index (ADIPO-IR) across the menstrual cycle were analysed using cosinor rhythmometry. Participants were assigned low or high categories of BMI, physical activity and cardiorespiratory fitness and category membership included in cosinor models as covariates. Results Rhythmicity was demonstrated by a significant cosine fit for glucose (p= 0.014) but not triglyceride (p= 0.369), insulin (p= 0.470), HOMA-IR (p=0.461) and ADIPO-IR (p= 0.335). When covariates were included, rhythmicity was observed when adjusting for: 1. BMI: glucose (p< 0.001), triglyceride (p< 0.001), insulin (p< 0.001), HOMA-IR (p< 0.001) and ADIPO-IR (p< 0.001); 2. Physical activity: glucose (p< 0.001), triglyceride (p= 0.006) and ADIPO-IR (p= 0.038); 3. Cardiorespiratory fitness: triglyceride (p= 0.041), insulin (p= 0.002), HOMA-IR (p= 0.004) and ADIPO-IR (p= 0.004). Triglyceride amplitude, but not acrophase, was greater in the high physical activity category compared to low (p=0.018). Conclusions Rhythmicity in insulin sensitivity and associated metabolites across the menstrual cycle are modified by BMI, physical activity and cardiorespiratory fitness
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