Accelerating the Mdx Heart Histo-Pathology through Physical Exercise.
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ABSTRACT:
SUBMITTER: Morroni J
PROVIDER: S-EPMC8306456 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The over-expression of NF-?B signalling in both muscle and immune cells contribute to the pathology in dystrophic muscle. The anti-inflammatory properties of glucocorticoids, mediated predominantly through monomeric glucocorticoid receptor inhibition of transcription factors such as NF-?B (transrepression), are postulated to be an important mechanism for their beneficial effects in Duchenne muscular dystrophy. Chronic glucocorticoid therapy is associated with adverse effects on metabolism, growth, bone mineral density and the maintenance of muscle mass. These detrimental effects result from direct glucocorticoid receptor homodimer interactions with glucocorticoid response elements of the relevant genes. Compound A, a non-steroidal selective glucocorticoid receptor modulator, is capable of transrepression without transactivation. We confirm the in vitro NF-?B inhibitory activity of compound A in H-2K(b) -tsA58 mdx myoblasts and myotubes, and demonstrate improvements in disease phenotype of dystrophin deficient mdx mice. Compound A treatment in mdx mice from 18 days of post-natal age to 8 weeks of age increased the absolute and normalized forelimb and hindlimb grip strength, attenuated cathepsin-B enzyme activity (a surrogate marker for inflammation) in forelimb and hindlimb muscles, decreased serum creatine kinase levels and reduced IL-6, CCL2, IFN?, TNF and IL-12p70 cytokine levels in gastrocnemius (GA) muscles. Compared with compound A, treatment with prednisolone, a classical glucocorticoid, in both wild-type and mdx mice was associated with reduced body weight, reduced GA, tibialis anterior and extensor digitorum longus muscle mass and shorter tibial lengths. Prednisolone increased osteopontin (Spp1) gene expression and osteopontin protein levels in the GA muscles of mdx mice and had less favourable effects on the expression of Foxo1, Foxo3, Fbxo32, Trim63, Mstn and Igf1 in GA muscles, as well as hepatic Igf1 in wild-type mice. In conclusion, selective glucocorticoid receptor modulation by compound A represents a potential therapeutic strategy to improve dystrophic pathology.
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Project description:Muscular dystrophy is characterized by muscle degeneration and insufficient regeneration and replacement of muscle fibers by connective tissue. New therapeutic strategies directed toward various forms of muscular dystrophy are needed to preserve muscle mass and promote regeneration. In this study we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle. We demonstrate that ADAM12 overexpression in the dystrophin-deficient mdx mice alleviated the muscle pathology in these animals, as evidenced by less muscle cell necrosis and inflammation, lower levels of serum creatine kinase, and less uptake of Evans Blue dye into muscle fibers. These studies demonstrate that ADAM12 directly or indirectly contributes to muscle cell regeneration, stability, and survival.
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Project description:Physical exercise training is a known protective factor against cardiovascular morbidity and mortality. Nevertheless, the underlying specific molecular mechanisms still remain uncompletely explored. To identify molecular mechanisms by which exercise training induces this favorable phenotype a genomic approach was used in an animal model of mild exercise previously demonstrated by our group to induce cardioprotection. Our data indicate that mild exercise by inducing no or few permanent changes in gene expression profile is able to determine cardioprotection without induction of cardiac hypertrophy. Keywords: Case-Control: Response to physical exsercise
2008-07-15 | GSE7640 | GEO
Project description:BackgroundDespite exercise being one of few strategies to improve outcomes for individuals with heart failure with preserved ejection fraction (HFpEF), exercise clinical trials in HFpEF are plagued by poor interventional adherence. Over the last 2 decades, our research team has developed, tested, and refined Heart failure Exercise And Resistance Training (HEART) Camp, a multicomponent behavioral intervention to promote adherence to exercise in HF. We evaluated the effects of this intervention designed to promote adherence to exercise in HF focusing on subgroups of participants with HFpEF and heart failure with reduced ejection fraction (HFrEF).Methods and resultsThis randomized controlled trial included 204 adults with stable, chronic HF. Of those enrolled, 59 had HFpEF and 145 had HFrEF. We tested adherence to exercise (defined as ≥120 minutes of moderate-intensity [40%-80% of heart rate reserve] exercise per week validated with a heart rate monitor) at 6, 12, and 18 months. We also tested intervention effects on symptoms (Patient-Reported Outcomes Measurement Information System-29 and dyspnea-fatigue index), HF-related health status (Kansas City Cardiomyopathy Questionnaire), and physical function (6-minute walk test). Participants with HFpEF (n = 59) were a mean of 64.6 ± 9.3 years old, 54% male, and 46% non-White with a mean ejection fraction of 55 ± 6%. Participants with HFpEF in the HEART Camp intervention group had significantly greater adherence compared with enhanced usual care at both 12 (43% vs 14%, phi = 0.32, medium effect) and 18 months (56% vs 0%, phi = 0.67, large effect). HEART Camp significantly improved walking distance on the 6-minute walk test (η2 = 0.13, large effect) and the Kansas City Cardiomyopathy Questionnaire overall (η2 = 0.09, medium effect), clinical summary (η2 = 0.16, large effect), and total symptom (η2 = 0.14, large effect) scores. In the HFrEF subgroup, only patient-reported anxiety improved significantly in the intervention group.ConclusionsA multicomponent, behavioral intervention is associated with improvements in long-term adherence to exercise, physical function, and patient-reported outcomes in adults with HFpEF and anxiety in HFrEF. Our results provide a strong rationale for a large HFpEF clinical trial to validate these findings and examine interventional mechanisms and delivery modes that may further promote adherence and improve clinical outcomes in this population.Clinical trial registrationURL: https://clinicaltrials.gov/. Unique identifier: NCT01658670.
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Project description:Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy affecting 1 in 3500 live male births. Although there is no cure for DMD, therapeutic strategies aimed at enhancing calcineurin signalling and promoting the slow fibre phenotype have shown promise in mdx mice, which is the classical mouse model for DMD. Sarcolipin (SLN) is a small protein that regulates the sarco(endo)plasmic reticulum Ca2+-ATPase pump and its expression is highly upregulated in dystrophic skeletal muscle. We have recently shown that SLN in skeletal muscle amplifies calcineurin signalling thereby increasing myofibre size and the slow fibre phenotype. Therefore, in the present study we sought to determine the physiological impact of genetic Sln deletion in mdx mice, particularly on calcineurin signalling, fibre-type distribution and size and dystrophic pathology. We generated an mdx/Sln-null (mdx/SlnKO) mouse colony and hypothesized that the soleus and diaphragm muscles from these mice would display blunted calcineurin signalling, smaller myofibre sizes, an increased proportion of fast fibres and worsened dystrophic pathology compared with mdx mice. Our results show that calcineurin signalling was impaired in mdx/SlnKO mice as indicated by reductions in utrophin, stabilin-2 and calcineurin expression. In addition, mdx/SlnKO muscles contained smaller myofibres, exhibited a slow-to-fast fibre-type switch that corresponded with reduced expression of mitochondrial proteins and displayed a worsened dystrophic pathology compared with mdx muscles. Altogether, our findings demonstrate a critical role for SLN upregulation in dystrophic muscles and suggest that SLN can be viewed as a potential therapeutic target.
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Project description:IntroductionAdults who engage in regular physical activity have lower rates of morbidity and mortality than those who do not. Exercise videogames may offer an attractive, sustainable alternative or supplement to traditional modes of exercise. This study compared exercise videogames with standard exercise modalities for improving uptake and maintenance of moderate to vigorous physical activity, and health risk indices.Study designA three-arm clinical RCT including 12 weeks of supervised laboratory-based moderate to vigorous physical activity followed by 6 months follow-up.Setting/participantsThis study was conducted at a university affiliated hospital research lab. Healthy, sedentary adults were eligible.InterventionsThis study compared a 12-week program of supervised exercise videogames versus standard exercise (e.g., treadmill) versus control. Data were collected from January 2012 to September 2017 and analyzed in 2018.Main outcome measuresThe primary outcome was weekly minutes of moderate to vigorous physical activity at end of treatment, assessed at 3 and 6 months post-intervention by using self-report and accelerometer data. Health risk indices (e.g., HbA1c, lipids) were also assessed.ResultsParticipants (N=283) had an average age of 46.2 ±13.5 years; 79% were female. At end of treatment, those in the exercise videogame arm engaged in 30 minutes/week more moderate to vigorous physical activity compared with standard exercise and 85 more minutes/week than controls (all p<0.05). Exercise videogame participants had greater reductions in cholesterol, HbA1c, and body fat versus other groups. Reductions in cholesterol were twice as large in exercise videogame versus standard participants.ConclusionsExercise videogames produced greater uptake and maintenance of moderate to vigorous physical activity compared with standard exercise and improvements in multiple health risk indices. Exercise videogames may promote sustainable physical activity with significant health benefits.Trial registrationThis study is registered at www.clinicaltrials.gov NCT03298919.
| S-EPMC7100962 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin and the subsequent disruption of the dystrophin-associated protein complex (DAPC). Utrophin is a dystrophin homolog expressed at high levels in developing muscle that is an attractive target for DMD therapy. Here we show that the extracellular matrix protein biglycan regulates utrophin expression in immature muscle and that recombinant human biglycan (rhBGN) increases utrophin expression in cultured myotubes. Systemically delivered rhBGN up-regulates utrophin at the sarcolemma and reduces muscle pathology in the mdx mouse model of DMD. RhBGN treatment also improves muscle function as judged by reduced susceptibility to eccentric contraction-induced injury. Utrophin is required for the rhBGN therapeutic effect. Several lines of evidence indicate that biglycan acts by recruiting utrophin protein to the muscle membrane. RhBGN is well tolerated in animals dosed for as long as 3 months. We propose that rhBGN could be a therapy for DMD.
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Project description:By targeting invasive organisms, antibiotics insert themselves into the ancient struggle of the host-pathogen evolutionary arms race. As pathogens evolve tactics for evading antibiotics, therapies decline in efficacy and must be replaced, distinguishing antibiotics from most other forms of drug development. Together with a slow and expensive antibiotic development pipeline, the proliferation of drug-resistant pathogens drives urgent interest in computational methods that promise to expedite candidate discovery. Strides in artificial intelligence (AI) have encouraged its application to multiple dimensions of computer-aided drug design, with increasing application to antibiotic discovery. This review describes AI-facilitated advances in the discovery of both small molecule antibiotics and antimicrobial peptides. Beyond the essential prediction of antimicrobial activity, emphasis is also given to antimicrobial compound representation, determination of drug-likeness traits, antimicrobial resistance, and de novo molecular design. Given the urgency of the antimicrobial resistance crisis, we analyze uptake of open science best practices in AI-driven antibiotic discovery and argue for openness and reproducibility as a means of accelerating preclinical research. Finally, trends in the literature and areas for future inquiry are discussed, as artificially intelligent enhancements to drug discovery at large offer many opportunities for future applications in antibiotic development.
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Project description:Background:Diabetes mellitus is a syndrome with multiple etiologies involving insulin, in which there is a lack of production and/or loss of sensitivity to this hormone resulting in insulin resistance. Treatment and control of this disease requires changes in diet, use of medication, and lifestyle, such as physical activity. These modifications may compromise quality-of-life if there is no proper guidance for the treatment or alert to possible complications caused by the disease. Methods:This study aimed to evaluate biochemical and hematological parameters, and to assess brain derived neurotrophic factor levels in diabetic Wistar rats submitted to chronic physical exercise. Results:The results demonstrated an increase in plasma concentration of brain-derived neurotrophic factor (BDNF) in association with hyperglycemia reduction in diabetic animals. Discussion:The results obtained suggest that there is a regulation of glucose homeostasis between peripheral tissues and the central nervous system. Exercise-induced BDNF also improved levels of glycemia, body weight, and dyslipidemia. In hematological evaluation, BDNF increase was positively correlated with an improvement in leukocyte parameters. Electrophoresis analyses demonstrated a reduction in levels of pro-inflammatory proteins, lipoprotein fractions, and albumin preservation in diabetic animals trained with elevated concentration of plasma BDNF. Conclusion:In conclusion, this study demonstrated that chronic exercise was able to elevate BDNF levels in plasma, which resulted directly in positive hypoglycemic activity in diabetic animals and a reduction of the metabolic syndrome associated with diabetes mellitus.
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Project description:It is challenging to compute structure-function relationships of proteins using molecular physics. The problem arises from the exponential scaling of the computational searching and sampling of large conformational spaces. This scaling challenge is not met by today's methods, such as Monte Carlo, simulated annealing, genetic algorithms, or molecular dynamics (MD) or its variants such as replica exchange. Such methods of searching for optimal states on complex probabalistic landscapes are referred to more broadly as Explore-and-Exploit (EE), including in contexts such as computational learning, games, industrial planning and modeling military strategies. Here we describe a Bayesian method, called MELD, that 'melds' together explore-and-exploit approaches with externally added information that can be vague, combinatoric, noisy, intuitive, heuristic, or from experimental data. MELD is shown to accelerate physical MD simulations when using experimental data to determine protein structures; for predicting protein structures by using heuristic directives; and when predicting binding affinities of proteins from limited information about the binding site. Such Guided Explore-and-Exploit approaches might also be useful beyond proteins and beyond molecular science.
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