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Exercise is fundamental for good health, whereas physical inactivity underpins many chronic diseases of modern society. It is well appreciated that regular exercise improves metabolism and the metabolic phenotype in a number of tissues. The phenotypic alterations observed in skeletal muscle are partly mediated by transcriptional responses that occur following each individual bout of exercise. This adaptive response increases oxidative capacity and influences the function of myokines and extracellular vesicles that signal to other tissues. Our understanding of the epigenetic and transcriptional mechanisms that mediate the skeletal muscle gene expression response to exercise as well as of their upstream signalling pathways has advanced substantially in the past 10 years. With this knowledge also comes the opportunity to design new therapeutic strategies based on the biology of exercise for a variety of chronic conditions where regular exercise might be a challenge. This Review provides an overview of the beneficial adaptive responses to exercise and details the molecular mechanisms involved. The possibility of designing therapeutic interventions based on these molecular mechanisms is addressed, using relevant examples that have exploited this approach.This Review highlights the beneficial adaptive responses to exercise in skeletal muscle and other tissues as well as their molecular mechanisms. In addition, the possibility of exercise-like therapeutic interventions is discussed, providing relevant examples that have used this approach.

It remains unclear as to whether polycystic ovary syndrome (PCOS) is an additional risk factor in the development of left ventricular (LV) hypertrophy in obese women. In the current study, we provide clarity on this issue by rigorously analysing patient LV geometry beyond the basic clinical measures currently used. Importantly, the cohort contained only normotensive patients that would normally be deemed low risk with no further intervention required. The study comprised 24 obese women with PCOS and 29 obese Control women. Transthoracic echocardiography was used to evaluate LV structure/function. Basic clinical and metabolic data were collected for each participant consisting of age, BMI, blood pressure, fasting glucose, LDL-C, HLD-C, cholesterol and triglyceride levels. Exclusion criteria; BMI < 30 g/m2, type 2 diabetes, hypertension. Both groups exhibited concentric remodelling of the LV posterior wall at a prevalence of ~20%, this associated with grade 1 diastolic dysfunction. Estimated LV mass/height2.7 was increased patients with PCOS (45 ± 2.2 vs 37 ± 1.6) with 33% exhibiting LV mass/height2.7 above ASE guidelines, compared to 7% in Controls. Furthermore, 25% of patients with PCOS were characterised with concentric hypertrophy, an alteration in LV geometry that was not observed in the Control group. To our knowledge, this is the first study to assess LV geometric patterns in obese women with PCOS. The results suggest that obese women with PCOS are at greater risk of concentric hypertrophy than obese only women and provide justification for additional cardiovascular risk assessment in normotensive obese/PCOS women.

The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy.

Background: Chlorinated phosphate esters (CPEs) are widely used as additive flame retardants for low-density polyurethane foams and have frequently been detected at elevated concentrations within indoor environmental media. Objectives: To begin characterizing the potential toxicity of CPEs on early vertebrate development, we examined the developmental toxicity of four CPEs used in polyurethane foam: tris(1,3-dichloro-2-propyl) phosphate (TDCPP), tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCPP), and 2,2-bis(chloromethyl)propane-1,3-diyl tetrakis(2-chlorethyl) bis(phosphate) (V6). Methods: Using zebrafish as a model for vertebrate embryogenesis, we first screened the potential teratogenic effects of TDCPP, TCEP, TCPP, and V6 using a developmental toxicity assay. Based on these results, we focused on identification of susceptible windows of developmental TDCPP exposure as well as evaluation of uptake and elimination of TDCPP and bis(1,3-dichloro-2-propyl) phosphate (BDCPP, the primary metabolite) within whole embryos. Finally, because TDCPP-specific genotoxicity assays have, for the most part, been negative in vivo and because zygotic genome remethylation is a key biological event during cleavage, we investigated whether TDCPP altered the status of zygotic genome methylation during early zebrafish embryogenesis. Results: Overall, our findings suggest that the cleavage period during zebrafish embryogenesis is susceptible to TDCPP-induced delays in remethylation of the zygotic genome, a mechanism that may be associated with enhanced developmental toxicity following initiation of TDCPP exposure at the start of cleavage. Conclusions: Our results suggest that further research is needed to better understand the effects of a widely used and detected CPE within susceptible windows of early vertebrate development.

Development of OA (OA) is multifactorial and is strongly associated with risk factors such as aging, trauma, metabolic disorders, and obesity. Metabolic Syndrome (MetS)-associated OA, collectively coined MetS-OA, is an increasingly recognized entity in which metabolic disorders and low-grade inflammation play a key mechanistic role in the disruption of joint homeostasis and cartilage degradation. Although there have been enormous efforts to discover biomarkers of MetS and OA, studies investigating a pathophysiological link between MetS and OA are relatively limited, and no serum blood marker has proved diagnostic so far. OA biomarkers that are necessary to discriminate and diagnose early disease remain to be elicited, explained in part by limited prospective studies, and therefore limited tools available to utilize in any prognostic capacity. Biomarker validation projects have been established by the Biomarker Consortium to determine biochemical markers demonstrating predictive validity for knee OA. Given that the metabolic constituents of MetS are treatable to varying extents, it stands to reason that treating these, and monitoring such treatment, may help to mitigate deleterious links with OA development. This narrative review will describe the current state of biomarker identification and utility in OA associated with MetS. We discuss the pathophysiological mechanisms of disease according to constituent pathologies of MetS and how identification of biomarkers may guide future investigation of novel targets.

As a first step toward understanding how rare variants contribute to risk for complex diseases, we sequenced 15,585 human protein-coding genes to an average median depth of 111 x in 2440 individuals of European (n = 1351) and African (n = 1088) ancestry. We identified over 500,000 single-nucleotide variants (SNVs), the majority of which were rare (86% with a minor allele frequency less than 0.5%), previously unknown (82%), and population-specific (82%). On average, 2.3% of the 13,595 SNVs each person carried were predicted to affect protein function of -313 genes per genome, and -95.7% of SNVs predicted to be functionally important were rare. This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits.

Metabolic syndrome (MetS) associated with Osteoarthritis (OA) is an increasingly recognised entity. Whilst the degenerative pattern in cuff-tear arthropathy (CTA) has been well documented, the biological processes behind primary shoulder OA and CTA remain less understood. This study investigates transcriptomic differences in these conditions, alongside the impact of MetS in patients undergoing total shoulder replacement. In a multi-centre study, 20 OA patients undergoing total shoulder replacement were included based on specific treatment indications for OA and cuff-tear arthropathy as well as 25 patients undergoing rotator cuff repair (RCR) as a comparator group. Tissues from subchondral bone, capsule (OA and RCR), and synovium were biopsied, and RNA sequencing was performed using Illumina platforms. Differential gene expression was conducted using DESeq2, adjusting for demographic factors, followed by pathway enrichment using the mitch package. Gene expressions in CTA and primary OA was differentially affected. CTA showed mitochondrial dysfunction, GATD3A downregulation, and increased cartilage degradation, while primary OA was marked by upregulated inflammatory and catabolic pathways. The effect of MetS on these pathologies was further shown. MetS further disrupted WNT/β-catenin signalling in CTA, and in OA. Genes such as ACAN, PANX3, CLU, and VAT1L were upregulated, highlighting potential biomarkers for early OA detection. This transcriptomic analysis reveals key differences between end-stage CTA and primary glenohumeral OA. CTA shows heightened metabolic/protein synthesis activity with less immune-driven inflammation. Under MetS, mitochondrial dysfunction (including GATD3A downregulation) and altered Wnt/β-catenin signalling intensify cartilage and bone damage. In contrast, primary OA features strong complement activation, inflammatory gene expression, and collagen remodelling. MetS worsens both conditions via oxidative stress, advanced glycation end products, and ECM disruption—particularly, increased CS/DS degradation. These distinctions support targeted treatments, from antioxidants and Wnt modulators to aggrecanase inhibitors or clusterin augmentation. Addressing specific molecular disruptions, especially those amplified by MetS, may preserve shoulder function, delay surgical intervention, and improve long-term patient outcomes.

Objective Osteoarthritis (OA) is a disease impacting the synovial joint complex, yet transcriptional changes specific to shoulder OA remain underexplored. This study aims to profile transcriptomic changes in periarticular tissues from patients undergoing shoulder replacement for OA. By correlating these profiles with QuickDASH scores—a validated measure of worsening shoulder function—this research seeks to understand the gene expression changes associated with clinical decline. Capsular tissue biopsies from shoulder OA patients were compared with those from a control group undergoing shoulder stabilization for recurrent instability. This investigation forms part of a larger transcriptomic analysis of painful shoulder conditions which will address the current gap in knowledge regarding the molecular and genetic underpinnings of shoulder OA, rotator cuff tears and cuff-tear arthropathy. Results The analysis revealed that genes most strongly associated with increasing QuickDASH scores across tissues were linked to inflammation and stress response. Key pathways involved interleukins, chemokines, complement components, nuclear response factors, and immediate early response genes, reflecting a balance between pro- and anti-inflammatory signalling. Additionally, this study identified unique gene expression patterns in shoulder OA not previously observed in hip and knee OA, along with novel genes implicated in shoulder OA, highlighting areas for future targeted investigation. Trial registration This investigation has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), registered on the 26th of March 2018, registration number: 12618000431224, accessible from: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374665&isReview=true

AMP-Activated Protein Kinase Regulates GLUT4 Transcription by Phosphorylating Histone Deacetylase 5 Sean L. McGee 1 2 , Bryce J.W. van Denderen 3 , Kirsten F. Howlett 2 , Janelle Mollica 2 , Jonathan D. Schertzer 1 , Bruce E. Kemp 3 4 and Mark Hargreaves 1 1 Department of Physiology, The University of Melbourne, Melbourne, Australia 2 School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia 3 St. Vincent’s Institute, Fitzroy, Australia 4 CSIRO Molecular and Health Technologies, Parkville, Australia Address correspondence and reprint requests to Sean McGee, Department of Physiology, The University of Melbourne, 3010, Australia. E-mail: slmcgee{at}unimelb.edu.au Abstract OBJECTIVE— Insulin resistance associated with obesity and diabetes is ameliorated by specific overexpression of GLUT4 in skeletal muscle. The molecular mechanisms regulating skeletal muscle GLUT4 expression remain to be elucidated. The purpose of this study was to examine these mechanisms. RESEARCH DESIGN AND METHODS AND RESULTS— Here, we report that AMP-activated protein kinase (AMPK) regulates GLUT4 transcription through the histone deacetylase (HDAC)5 transcriptional repressor. Overexpression of HDAC5 represses GLUT4 reporter gene expression, and HDAC inhibition in human primary myotubes increases endogenous GLUT4 gene expression. In vitro kinase assays, site-directed mutagenesis, and site-specific phospho-antibodies establish AMPK as an HDAC5 kinase that targets S259 and S498. Constitutively active but not dominant-negative AMPK and 5-aminoimidazole-4-carboxamide-1-β- d -ribonucleoside (AICAR) treatment in human primary myotubes results in HDAC5 phosphorylation at S259 and S498, association with 14-3-3 isoforms, and H3 acetylation. This reduces HDAC5 association with the GLUT4 promoter, as assessed through chromatin immunoprecipitation assays and HDAC5 nuclear export, concomitant with increases in GLUT4 gene expression. Gene reporter assays also confirm that the HDAC5 S259 and S498 sites are required for AICAR induction of GLUT4 transcription. CONCLUSIONS— These data reveal a signal transduction pathway linking cellular energy charge to gene transcription directed at restoring cellular and whole-body energy balance and provide new therapeutic targets for the treatment and management of insulin resistance and type 2 diabetes. AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside AMPK, AMP-activated protein kinase CaMK, calcium/calmodulin-dependent protein kinases ChIP, chromatin immunoprecipitation GEF, GLUT4 enhancer factor H3, histone 3 H3K9, histone 3 lysine 9 HAT, histone acetyl-transferase HDAC, histone deacetylase MEF, myocyte enhancer factor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 9 January 2007. DOI: 10.2337/db07-0843. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0843 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 1, 2008. Received June 20, 2007. DIABETES

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer’s disease. The role of amyloid beta 42 (Aβ 42 ) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aβ 42 , which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aβ 42 . Increasing circulating Aβ 42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aβ 40 isoform does not have these same effects on the heart. Administration of an Aβ-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aβ-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aβ 42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aβ 42 inhibits mitochondrial complex I. These data reveal a role for systemic Aβ 42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer’s disease could be effective in combating obesity-induced heart failure. Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.