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Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy.

BACKGROUND: Biased agonism of the angiotensin II receptor is known to promote cardiac contractility. Our laboratory indicated that these effects may be attributable to changes at the level of the myofilaments. However, these signaling mechanisms remain unknown. Because a common finding in dilated cardiomyopathy is a reduction in the myofilament-Ca2+ response, we hypothesized that β-arrestin signaling would increase myofilament-Ca2+ responsiveness in a model of familial dilated cardiomyopathy and improve cardiac function and morphology. METHODS: We treated a dilated cardiomyopathy-linked mouse

Translocation of molecular chaperones to the titin springs is common in skeletal myopathy patients and affects sarcomere function.

Myopathies encompass a wide variety of acquired and hereditary disorders. The pathomechanisms include structural and functional changes affecting, e.g., myofiber metabolism and contractile properties. In this study, we observed increased passive tension (PT) of skinned myofibers from patients with myofibrillar myopathy (MFM) caused by FLNC mutations (MFM-filaminopathy) and limb-girdle muscular dystrophy type-2A due to CAPN3 mutations (LGMD2A), compared to healthy control myofibers. Because the giant protein titin determines myofiber PT, we measured its molecular size and the titin-to-myosin ra

Studying Dynamic Myofiber Aggregate Reorientation in Dilated Cardiomyopathy Using In Vivo Magnetic Resonance Diffusion Tensor Imaging.

BACKGROUND: The objective of this study is to assess the dynamic alterations of myocardial microstructure and strain between diastole and systole in patients with dilated cardiomyopathy relative to healthy controls using the magnetic resonance diffusion tensor imaging, myocardial tagging, and biomechanical modeling. METHODS AND RESULTS: Dual heart-phase diffusion tensor imaging was successfully performed in 9 patients and 9 controls. Tagging data were acquired for the diffusion tensor strain correction and cardiac motion analysis. Mean diffusivity, fractional anisotropy, and myocyte aggregate

Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy.

Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca(2+) from internal stores to initiate muscle contraction. Defects in excitation-contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation-contraction coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3. We provide electrophysiological, Ca(2+) imaging, immunocytochemical and biochemical evidence that Stac3 participates

Ablation of p21-activated kinase-1 in mice promotes isoproterenol-induced cardiac hypertrophy in association with activation of Erk1/2 and inhibition of protein phosphatase 2A.

Earlier investigations in our lab indicated an anti-adrenergic effect induced by activation of p21-activated kinase (Pak-1) and protein phosphatase 2A (PP2A). Our objective was to test the hypothesis that Pak-1/PP2A is a signaling cascade controlling stress-induced cardiac growth. We determined the effects of ablation of the Pak-1 gene on the response of the myocardium to chronic stress of isoproterenol (ISO) administration. Wild-type (WT) and Pak-1-knockout (Pak-1-KO) mice were randomized into six groups to receive either ISO, saline (CTRL), or ISO and FR180204, a selective inhibitor of Erk1/

Перепрофилированный активатор Nrf2 диметилфумарат спасает мышцы воспаление и фиброз в отягченной мышиной модели мышечной дистрофии Дученна.

В унаследованных нейромускульных болезнях мышечная дистрофия Дюченна (ДМД) глюкокортикоиды значительно медленнее прогрессируют, но в то же время создают достаточно серьезные побочные эффекты, исключающие применение в значительной части пациентов. Распространяя наши выводы о том, что в результате острого лечения с УЛХ были одобрены многочисленные склерозные препараты, диметилфумарат (ДМФ), спасающая мышечную патологию у молодых мышей Mdx, мы намеревались провести доклиническое тестирование на перевод. Чтобы усилить фенотип болезни у взрослых мышц mdx, у которых обычно нет эквивалентной человече

Right Ventricle Has Normal Myofilament Function But Shows Perturbations in the Expression of Extracellular Matrix Genes in Patients With Tetralogy of Fallot Undergoing Pulmonary Valve Replacement.

Background Patients with repair of tetralogy of Fallot (rToF) who are approaching adulthood often exhibit pulmonary valve regurgitation, leading to right ventricle (RV) dilatation and dysfunction. The regurgitation can be corrected by pulmonary valve replacement (PVR), but the optimal surgical timing remains under debate, mainly because of the poorly understood nature of RV remodeling in patients with rToF. The goal of this study was to probe for pathologic molecular, cellular, and tissue changes in the myocardium of patients with rToF at the time of PVR. Methods and Results We measured contra

Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.

BACKGROUND: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. METHODS AND RESULTS: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-myosin heavy chain promoter. Cardiac structure asse

Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.

RATIONALE: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. OBJECTIVE: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. METHODS AND RESULTS: Cardiac samples from patients with HCM h

Activation of ubiquitin-proteasome pathway is involved in skeletal muscle wasting in a rat model with biliary cirrhosis: potential role of TNF-alpha.

Vitamin A deficiency is one of the most common dietary deficiencies in the developing world and is a major health concern where it is associated with increased risk of fetal and infant mortality and morbidity. Early studies in the rat demonstrated that, in addition to respiratory problems, neonates showed evidence of mobility problems in response to moderate vitamin A deficiency. This study investigated whether moderate deficiency of this vitamin plays a role in regulating key skeletal muscle regulatory pathways during development. Thirty female rats were fed vitamin A-moderate (VAM) or vitami

Transcriptome Analysis and Experimental Validation of Palmitoylation- Related Biomarkers in Atherosclerosis.

INTRODUCTION: Protein palmitoylation contributes to membrane localisation, signal transduction, and cell-fate regulation. It is closely associated with lipid metabolic dysfunction, immune inflammation, and vascular remodelling in atherosclerosis (AS). However, key palmitoylation-related transcriptomic markers and their potential causal associations with AS remain incompletely defined. METHODS: The Gene Expression Omnibus (GEO) dataset GSE100927 was used as the training cohort, and GSE43292 was used as an external validation cohort. Differentially expressed genes were identified using limma an

[Effect of acupuncture pretreatment on PINK1/Parkin pathway-mediated mitophagy in rats with exercise-induced muscle damage].

OBJECTIVE: Based on the PTEN-induced hypothetical kinase 1 (PINK1)/Parkin pathway, the effect of acupuncture pretreatment on the expression of mitochondrial autophagy-related proteins in gastrocnemius muscle tissue of rats with exercise-induced muscle damage (EIMD) was observed, and the underlying mechanism of acupuncture pretreatment for the prevention and treatment of EIMD was explored. METHODS: Of 88 SD male rats, aged 6 weeks, 8 rats were randomly selected as a blank group, and the remaining 80 rats were randomized into a model group and an acupuncture pretreatment group, with 40 rats in

Halofuginone improves muscle-cell survival in muscular dystrophies.

Halofuginone has been shown to prevent fibrosis via the transforming growth factor-β/Smad3 pathway in muscular dystrophies. We hypothesized that halofuginone would reduce apoptosis--the presumed cause of satellite-cell depletion during muscle degradation-in the mdx mouse model of Duchenne muscular dystrophy. Six-week-old mdx mouse diaphragm exhibited fourfold higher numbers of apoptotic nuclei compared with wild-type mice as determined by a TUNEL assay. Apoptotic nuclei were found in macrophages and in Pax7-expressing cells; some were located in centrally-nucleated regenerating myofibers. Halo

Eccentric Resistance Training Ameliorates Muscle Weakness in a Mouse Model of Idiopathic Inflammatory Myopathies.

OBJECTIVE: High-force eccentric contractions (ECCs) have traditionally been excluded from rehabilitation programs that include patients with idiopathic inflammatory myopathies (IIMs) due to unverified fear of causing muscle damage and inflammation. In an IIM animal model that used mice with experimental autoimmune myositis (EAM), we undertook this study to investigate whether ECC training can safely and effectively be used to counteract muscle weakness in IIM. METHODS: EAM was induced in BALB/c mice by immunization with 3 injections of myosin emulsified in Freund's complete adjuvant. Controls

Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity.

BACKGROUND: Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds. METHODS AND RESULTS: Action potential duratio

Myofibrillar protein accumulation but reduced protein synthesis in PDCD4-depleted myotubes.

Skeletal muscle is critical to whole-body functionality and homeostasis. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient/growth-factor sensitive positive regulator of skeletal muscle mass. Amongst other substrates, mTORC1 phosphorylates the ribosomal protein S6 kinase (S6K1). Activated S6K1 acts through multiple effectors, including programmed cell death 4 (PDCD4), to promote mRNA translation and protein synthesis. Much of what is known about PDCD4 is in non-muscle cells. We previously demonstrated that the effect of PDCD4 differs between myoblasts and myotubes.

Endothelin-1 induces myofibrillar disarray and contractile vector variability in hypertrophic cardiomyopathy-induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate t

Emerging Strategies Targeting Catabolic Muscle Stress Relief.

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. Thi

Совпадение в полном тексте источника
… The calcineurin-FoxO-MuRF1 signaling pathway regulates myofibril integrity in cardiomyocytes eLife 2017 6 1 19 10.7554/eLife.27955 28826496 PMC5576919 60. Jamart C. Raymackers J.M. An G.L. Deldicque L. Francaux M. … Transient association of titin and myosin with microtubules in nascent myofibrils directed by the MURF2 RING-finger protein J. Cell Sci. 2002 115 4469 4482 10.1242/jcs.00131 12414993 92. Mayans O. Labeit S. …

A Case of Elevated Troponin I Level After Packed Red Blood Cell Transfusion With Normal Coronary Angiography.

Other than acute coronary syndrome (ACS), many clinical conditions are associated with increased cardiac troponin I (cTnI) levels. Conditions such as pulmonary embolism, acute heart failure, myocarditis, sepsis, and renal failure are commonly reported as underlying causes. Analytical interference with the cTnI assay can also lead to falsely elevated troponin I levels. That can happen due to multiple causes such as fibrin clots, heterophile antibodies, microparticles contained in the sample, rheumatoid factor, interference by bilirubin, hemolysis, and elevated alkaline phosphatase activity. Her

Совпадение в полном тексте источника
… Discussion Troponin is a protein complex with three regulatory gene products and is located on the thin filaments of myofibrils. Cardiac troponin C binds calcium, cardiac troponin T attaches to tropomyosin on thin filaments, and cTnI inhibits actomyosin ATPase. …

LEOPARD-type SHP2 mutant Gln510Glu attenuates cardiomyocyte differentiation and promotes cardiac hypertrophy via dysregulation of Akt/GSK-3β/β-catenin signaling.

LEOPARD syndrome (LS) is an autosomal dominant inherited multisystemic disorder. Most cases involve mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase Src homology 2-containing protein phosphatase 2 (SHP2). LS frequently causes severe hypertrophic cardiomyopathy (HCM), even from the fetal period. However, the molecular pathogenesis has not been clearly elucidated. Here, we analyzed the roles of the LS-type SHP2 mutant Gln510Glu (Q510E), which showed the most severe type of HCM in LS, in cardiomyocyte differentiation, and in morphological changes. We generated mutant P