-
Open Biology Jun 2024Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here,...
Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here, we generated transgenic MYH7 R453C and MYH6 R453C piglets and found both developed typical cardiac hypertrophy. Unexpectedly, we found serious fibrosis and cardiomyocyte loss in the ventricular of MYH7 R453C, not MYH6 R453C piglets, similar to HCM patients. Then, RNA-seq analysis and western blotting identified the activation of ERK1/2 and PI3K-Akt pathways in MYH7 R453C. Moreover, we observed an increased expression of fetal genes and an excess of reactive oxygen species (ROS) in MYH7 R453C piglet models, which was produced by Nox4 and subsequently induced inflammatory response. Additionally, the phosphorylation levels of Smad2/3, ERK1/2 and NF-kB p65 proteins were elevated in cardiomyocytes with the MYH7 R453C mutation. Furthermore, epigallocatechin gallate, a natural bioactive compound, could be used as a drug to reduce cell death by adjusting significant downregulation of the protein expression of Bax and upregulated Bcl-2 levels in the H9C2 models with MYH7 R453C mutation. In conclusion, our study illustrated that TGF-β/Smad2/3, ERK1/2 and Nox4/ROS pathways have synergistic effects on cardiac remodelling and inflammation in MYH7 R453C mutation.
Topics: Animals; Myosin Heavy Chains; Transforming Growth Factor beta; NADPH Oxidase 4; Reactive Oxygen Species; NF-kappa B; Signal Transduction; Swine; Myocytes, Cardiac; Humans; Cardiac Myosins; Disease Models, Animal; MAP Kinase Signaling System; Animals, Genetically Modified; Smad2 Protein; Mutation; Smad3 Protein; Ventricular Remodeling; Cardiomyopathy, Hypertrophic; Rats
PubMed: 38862020
DOI: 10.1098/rsob.230427 -
American Journal of Physiology. Lung... Jun 2024Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the...
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but its role in PAH is unsettled. Here, we report that: (1) PAI-1 is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared to controls; (2) PAI-1 mice spontaneously develop pulmonary vascular remodeling associated with up-regulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and (3) pharmacological inhibition of uPA in human PAH PASMCs suppresses pro-proliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation and induces apoptosis , and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in mice. These data strongly suggest that down-regulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent up-regulation of mTOR and TGF-b signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH.
PubMed: 38860847
DOI: 10.1152/ajplung.00110.2024 -
Cureus May 2024The presence of a supernumerary subserosal muscle layer of the bowel is an extremely unusual congenital development. The following is a report of diffuse involvement of...
The presence of a supernumerary subserosal muscle layer of the bowel is an extremely unusual congenital development. The following is a report of diffuse involvement of the intestine with a supernumerary subserosal muscle coat. The current patient, a 29-year-old male, was evaluated in January 2022 for a long-standing history of subacute intestinal obstruction (SAIO). A preoperative CT scan of the abdomen and pelvis suggested mild dilatation and clumping of ileal loops in the right iliac fossa, with a subtle wall thickening of up to 5 mm. Intraoperatively, dense adhesions were noted between clumped bowel loops and the anterior abdominal wall. Following adhesiolysis, ileocecal resection with ileocolic anastomosis was done. The histopathological examination of the resected bowel segment showed irregular hypertrophy of circular and longitudinal muscle layers with the presence of an additional smooth muscle coat outer to the outer longitudinal layer that was seen in the ileum as well as the appendix. No evidence of vacuolar degeneration was noted, and ganglion cells were seen to be adequately present. The presence of additional smooth muscle bundles in the subserosa was confirmed with positive actin immunostaining. Additionally, CD117 staining was done that revealed a normal network of interstitial cells of Cajal. No evidence of active inflammation was noted in the resected bowel segment. Findings from the current case bring to light an extremely rare malformation of the muscularis propria of the intestine, namely a supernumerary subserosal muscle coat.
PubMed: 38860074
DOI: 10.7759/cureus.60096 -
SAGE Open Medical Case Reports 2024Whey protein and other protein-fortified supplements are frequently consumed as nutritional supplements to aid in muscle hypertrophy and myogenesis. This case presents a...
Whey protein and other protein-fortified supplements are frequently consumed as nutritional supplements to aid in muscle hypertrophy and myogenesis. This case presents a 36-year-old athletic male with elevated creatinine and uric acid levels during routine laboratory evaluation. The patient had no history of kidney disease, diabetes, or hypertension. It was revealed that the patient had been regularly consuming whey protein as a dietary supplement for 2 months. Given the potential association between the elevated creatinine and uric acid levels and the use of whey protein, the patient was advised to discontinue the supplement. The patient then switched to protein-fortified milk to mitigate the possible harmful connection between the dietary intake and the laboratory findings. However, despite the dietary change, the increased levels of creatinine and uric acid persisted. This observation suggests that the elevated levels may be attributed to chronic whey protein consumption along with high-protein dietary consumption.
PubMed: 38859872
DOI: 10.1177/2050313X241260229 -
BMC Genomics Jun 2024Understanding growth regulatory pathways is important in aquaculture, fisheries, and vertebrate physiology generally. Machine learning pattern recognition and...
BACKGROUND
Understanding growth regulatory pathways is important in aquaculture, fisheries, and vertebrate physiology generally. Machine learning pattern recognition and sensitivity analysis were employed to examine metabolomic small molecule profiles and transcriptomic gene expression data generated from liver and white skeletal muscle of hybrid striped bass (white bass Morone chrysops x striped bass M. saxatilis) representative of the top and bottom 10 % by body size of a production cohort.
RESULTS
Larger fish (good-growth) had significantly greater weight, total length, hepatosomatic index, and specific growth rate compared to smaller fish (poor-growth) and also had significantly more muscle fibers of smaller diameter (≤ 20 µm diameter), indicating active hyperplasia. Differences in metabolomic pathways included enhanced energetics (glycolysis, citric acid cycle) and amino acid metabolism in good-growth fish, and enhanced stress, muscle inflammation (cortisol, eicosanoids) and dysfunctional liver cholesterol metabolism in poor-growth fish. The majority of gene transcripts identified as differentially expressed between groups were down-regulated in good-growth fish. Several molecules associated with important growth-regulatory pathways were up-regulated in muscle of fish that grew poorly: growth factors including agt and agtr2 (angiotensins), nicotinic acid (which stimulates growth hormone production), gadd45b, rgl1, zfp36, cebpb, and hmgb1; insulin-like growth factor signaling (igfbp1 and igf1); cytokine signaling (socs3, cxcr4); cell signaling (rgs13, rundc3a), and differentiation (rhou, mmp17, cd22, msi1); mitochondrial uncoupling proteins (ucp3, ucp2); and regulators of lipid metabolism (apoa1, ldlr). Growth factors pttg1, egfr, myc, notch1, and sirt1 were notably up-regulated in muscle of good-growing fish.
CONCLUSION
A combinatorial pathway analysis using metabolomic and transcriptomic data collectively suggested promotion of cell signaling, proliferation, and differentiation in muscle of good-growth fish, whereas muscle inflammation and apoptosis was observed in poor-growth fish, along with elevated cortisol (an anti-inflammatory hormone), perhaps related to muscle wasting, hypertrophy, and inferior growth. These findings provide important biomarkers and mechanisms by which growth is regulated in fishes and other vertebrates as well.
Topics: Animals; Bass; Female; Gene Expression Profiling; Male; Metabolomics; Muscle Development; Transcriptome; Muscle, Skeletal; Metabolome; Liver
PubMed: 38858615
DOI: 10.1186/s12864-024-10325-y -
Medicine and Science in Sports and... Jun 2024The hamstring muscles play a crucial role in sprint running, but are also highly susceptible to strain injuries, particularly within the biceps femoris long head (BFlh)....
INTRODUCTION
The hamstring muscles play a crucial role in sprint running, but are also highly susceptible to strain injuries, particularly within the biceps femoris long head (BFlh). This study compared the adaptations in muscle size and strength of the knee flexors, as well as BFlh muscle and aponeurosis size, after two eccentrically focused knee flexion training regimes: Nordic hamstring training (NHT) or lengthened state eccentric training (LSET, isoinertial weight-stack resistance in an accentuated hip-flexed position), to habitual activity (no training controls: CON).
METHODS
42 healthy young males completed 34 sessions of NHT or LSET over 12 weeks or served as CON (n = 14/group). MRI-measured muscle volume of seven individual knee flexors and BFlh aponeurosis area, and maximum knee flexion torque during eccentric, concentric and isometric contractions were assessed pre- and post-training.
RESULTS
LSET induced greater increases in hamstrings (+18% vs +11%) and BFlh (+19% vs +5%) muscle volumes and BFlh aponeurosis area (+9% vs +3%) than NHT (all P ≤ 0.001), with no changes after CON. There were distinctly different patterns of hypertrophy between the two training regimes, largely due to the functional role of the muscles; LSET was more effective for increasing the size of knee flexors that also extend the hip (2.2-fold vs NHT), whereas NHT increased the size of knee flexors that do not extend the hip (1.9-fold vs LSET; both P ≤ 0.001). Changes in maximum eccentric torque differed only between LSET and CON (+17% vs +4%; P = 0.009), with NHT (+11%) in-between.
CONCLUSIONS
These results suggest that LSET is superior to NHT in inducing overall hamstrings and BFlh hypertrophy, potentially contributing to better sprint performance improvements and protection against hamstring strain injuries than NHT.
PubMed: 38857522
DOI: 10.1249/MSS.0000000000003490 -
Juntendo Iji Zasshi = Juntendo Medical... 2023This study aimed to determine the effects of high-intensity isokinetic training with blood flow restriction during rest interval between set (rBFR) versus during...
OBJECTIVES
This study aimed to determine the effects of high-intensity isokinetic training with blood flow restriction during rest interval between set (rBFR) versus during exercise (eBFR) on muscle hypertrophy and increasing muscle strength and determine whether BFR-induced exercise pain is suppressed by rBFR.
MATERIALS AND METHODS
Fourteen arms (7 participants) were recruited for the study. We conducted the following interventions for each arm: eBFR (n=4), rBFR (n=5), and exercise only (CON, n=5). The participants performed elbow flexion training with a BIODEX device twice weekly for 8 weeks. This study training consisted of total four sets; each was performed until <50% peak torque was achieved twice consecutively. BFR pressure was set at 120 mmHg. Elbow flexor peak torque during concentric contraction (CC), isometric contraction (IM), and muscle cross-sectional area (CSA) were measured before and after the intervention. Numerical rating scale scores used to assess pain during exercise were determined during training.
RESULTS
Peak torque at the CC increased in the rBFR (p<0.05) and IM increased in the rBFR and CON (p<0.05), while CSA increased in the rBFR and CON (p<0.001). The pain during exercise was severe in the eBFR and moderate in the rBFR and CON.
CONCLUSIONS
This study's showed that high-intensity isokinetic training with rBFR did not have a synergistic effect on increasing muscle strength and muscle size. Additionally, high-intensity isokinetic training with BFR when it may be best not to perform it during exercise, because it was induces severe pain and may inhibit increases in muscle strength.
PubMed: 38855068
DOI: 10.14789/jmj.JMJ23-0014-OA -
Circulation. Genomic and Precision... Jun 2024Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations...
Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy.
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations (genotype-negative HCM) in the other half of patients. We explored how alterations in the metabolomic and lipidomic landscape are involved in cardiac remodeling in both patient groups.
METHODS
We performed proteomics, metabolomics, and lipidomics on myectomy samples (genotype-positive N=19; genotype-negative N=22; and genotype unknown N=6) from clinically well-phenotyped patients with HCM and on cardiac tissue samples from sex- and age-matched and body mass index-matched nonfailing donors (N=20). These data sets were integrated to comprehensively map changes in lipid-handling and energy metabolism pathways. By linking metabolomic and lipidomic data to variability in clinical data, we explored patient group-specific associations between cardiac and metabolic remodeling.
RESULTS
HCM myectomy samples exhibited (1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage. In genotype-negative patients, septal hypertrophy and diastolic dysfunction correlated with lowering of acylcarnitines, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines. In contrast, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines were positively associated with septal hypertrophy and diastolic impairment in genotype-positive patients.
CONCLUSIONS
We provide novel insights into both general and genotype-specific metabolic changes in HCM. Distinct metabolic alterations underlie cardiac disease progression in genotype-negative and genotype-positive patients with HCM.
Topics: Humans; Cardiomyopathy, Hypertrophic; Male; Female; Middle Aged; Genotype; Adult; Phenotype; Myocardium; Metabolomics; Proteomics; Lipidomics; Lipid Metabolism; Sarcomeres; Energy Metabolism; Aged; Multiomics
PubMed: 38853772
DOI: 10.1161/CIRCGEN.123.004369 -
Journal of Cellular and Molecular... Jun 2024Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by pulmonary and systemic congestion resulting from left ventricular...
Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by pulmonary and systemic congestion resulting from left ventricular diastolic dysfunction and increased filling pressure. Currently, however, there is no evidence on effective pharmacotherapy for HFpEF. In this study, we aimed to investigate the therapeutic effect of total xanthones extracted from Gentianella acuta (TXG) on HFpEF by establishing an high-fat diet (HFD) + L-NAME-induced mouse model. Echocardiography was employed to assess the impact of TXG on the cardiac function in HFpEF mice. Haematoxylin and eosin staining, wheat germ agglutinin staining, and Masson's trichrome staining were utilized to observe the histopathological changes following TXG treatment. The results demonstrated that TXG alleviated HFpEF by reducing the expressions of genes associated with myocardial hypertrophy, fibrosis and apoptosis. Furthermore, TXG improved cardiomyocyte apoptosis by inhibiting the expression of apoptosis-related proteins. Mechanistic investigations revealed that TXG could activate the inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (Xbp1s) signalling pathway, but the knockdown of IRE1α using the IRE1α inhibitor STF083010 or siRNA-IRE1α impaired the ability of TXG to ameliorate cardiac remodelling in HFpEF models. In conclusion, TXG alleviates myocardial hypertrophy, fibrosis and apoptosis through the activation of the IRE1α/Xbp1s signalling pathway, suggesting its potential beneficial effects on HFpEF patients.
Topics: Animals; Endoribonucleases; Heart Failure; X-Box Binding Protein 1; Protein Serine-Threonine Kinases; Signal Transduction; Mice; Male; Xanthones; Apoptosis; Disease Models, Animal; Mice, Inbred C57BL; Myocytes, Cardiac; Diet, High-Fat; Fibrosis; Stroke Volume
PubMed: 38847482
DOI: 10.1111/jcmm.18466 -
Circulation. Genomic and Precision... Jun 2024Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel...
BACKGROUND
Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM.
METHODS
Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels.
RESULTS
Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; =0.044).
CONCLUSIONS
In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.
Topics: Humans; Cardiomyopathy, Hypertrophic; Biomarkers; Child; Female; Male; Child, Preschool; Adolescent; Prognosis; Proteomics; Infant; Adult
PubMed: 38847081
DOI: 10.1161/CIRCGEN.123.004448