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Cardiovascular Diabetology Jun 2024The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune...
Y4 RNA fragments from cardiosphere-derived cells ameliorate diabetic myocardial ischemia‒reperfusion injury by inhibiting protein kinase C β-mediated macrophage polarization.
The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cβ (PKCβ) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCβ activation. The mechanism by which Y4 RNA affects PKCβ by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCβ in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCβ knockout mice. Our findings indicate that PKCβ plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCβ expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCβ/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.
Topics: Animals; Protein Kinase C beta; Myocardial Reperfusion Injury; Macrophages; Disease Models, Animal; Male; Mice, Inbred C57BL; Signal Transduction; Interleukin-10; Mice; Diabetic Cardiomyopathies; Cells, Cultured; Phenotype; Myocytes, Cardiac; Mitogen-Activated Protein Kinase 3; Macrophage Activation; Mitogen-Activated Protein Kinase 1; Ventricular Function, Left; Phosphorylation
PubMed: 38867293
DOI: 10.1186/s12933-024-02247-6 -
Molecular Medicine (Cambridge, Mass.) Jun 2024The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The...
BACKGROUND
The terminal stage of ischemic heart disease develops into heart failure (HF), which is characterized by hypoxia and metabolic disturbances in cardiomyocytes. The hypoxic failing heart triggers hypoxia-inducible factor-1α (HIF-1α) actions in the cells sensitized to hypoxia and induces metabolic adaptation by accumulating HIF-1α. Furthermore, soluble monocarboxylic acid transporter protein 1 (MCT1) and mitochondrial pyruvate carrier 1 (MPC1), as key nodes of metabolic adaptation, affect metabolic homeostasis in the failing rat heart. Aerobic exercise training has been reported to retard the progression of HF due to enhancing HIF-1α levels as well as MCT1 expressions, whereas the effects of exercise on MCT1 and MPC1 in HF (hypoxia) remain elusive. This research aimed to investigate the action of exercise associated with MCT1 and MPC1 on HF under hypoxia.
METHODS
The experimental rat models are composed of four study groups: sham stented (SHAM), HF sedentary (HF), HF short-term exercise trained (HF-E1), HF long-term exercise trained (HF-E2). HF was initiated via left anterior descending coronary artery ligation, the effects of exercise on the progression of HF were analyzed by ventricular ultrasound (ejection fraction, fractional shortening) and histological staining. The regulatory effects of HIF-1α on cell growth, MCT1 and MPC1 protein expression in hypoxic H9c2 cells were evaluated by HIF-1α activatort/inhibitor treatment and plasmid transfection.
RESULTS
Our results indicate the presence of severe pathological remodelling (as evidenced by deep myocardial fibrosis, increased infarct size and abnormal hypertrophy of the myocardium, etc.) and reduced cardiac function in the failing hearts of rats in the HF group compared to the SHAM group. Treadmill exercise training ameliorated myocardial infarction (MI)-induced cardiac pathological remodelling and enhanced cardiac function in HF exercise group rats, and significantly increased the expression of HIF-1α (p < 0.05), MCT1 (p < 0.01) and MPC1 (p < 0.05) proteins compared to HF group rats. Moreover, pharmacological inhibition of HIF-1α in hypoxic H9c2 cells dramatically downregulated MCT1 and MPC1 protein expression. This phenomenon is consistent with knockdown of HIF-1α at the gene level.
CONCLUSION
The findings propose that long-term aerobic exercise training, as a non- pharmacological treatment, is efficient enough to debilitate the disease process, improve the pathological phenotype, and reinstate cardiac function in HF rats. This benefit is most likely due to activation of myocardial HIF-1α and upregulation of MCT1 and MPC1.
Topics: Animals; Male; Rats; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Myocytes, Cardiac; Physical Conditioning, Animal; Rats, Sprague-Dawley; Symporters; Up-Regulation
PubMed: 38867145
DOI: 10.1186/s10020-024-00854-3 -
BMC Genomics Jun 2024The skeletal muscle growth rate and body size of Tibetan pigs (TIB) are lower than Large white pigs (LW). However, the underlying genetic basis attributing to these...
BACKGROUND
The skeletal muscle growth rate and body size of Tibetan pigs (TIB) are lower than Large white pigs (LW). However, the underlying genetic basis attributing to these differences remains uncertain. To address this knowledge gap, the present study employed whole-genome sequencing of TIB (slow growth) and LW (fast growth) individuals, and integrated with existing NCBI sequencing datasets of TIB and LW individuals, enabling the identification of a comprehensive set of genetic variations for each breed. The specific and predominant SNPs in the TIB and LW populations were detected by using a cutoff value of 0.50 for SNP allele frequency and absolute allele frequency differences (△AF) between the TIB and LW populations.
RESULTS
A total of 21,767,938 SNPs were retrieved from 44 TIB and 29 LW genomes. The analysis detected 2,893,106 (13.29%) and 813,310 (3.74%) specific and predominant SNPs in the TIB and LW populations, and annotated to 24,560 genes. Further GO analysis revealed 291 genes involved in biological processes related to striated and/or skeletal muscle differentiation, proliferation, hypertrophy, regulation of striated muscle cell differentiation and proliferation, and myoblast differentiation and fusion. These 291 genes included crucial regulators of muscle cell determination, proliferation, differentiation, and hypertrophy, such as members of the Myogenic regulatory factors (MRF) (MYOD, MYF5, MYOG, MYF6) and Myocyte enhancer factor 2 (MEF2) (MEF2A, MEF2C, MEF2D) families, as well as muscle growth inhibitors (MSTN, ACVR1, and SMAD1); KEGG pathway analysis revealed 106 and 20 genes were found in muscle growth related positive and negative regulatory signaling pathways. Notably, genes critical for protein synthesis, such as MTOR, IGF1, IGF1R, IRS1, INSR, and RPS6KA6, were implicated in these pathways.
CONCLUSION
This study employed an effective methodology to rigorously identify the potential genes associated with skeletal muscle development. A substantial number of SNPs and genes that potentially play roles in the divergence observed in skeletal muscle growth between the TIB and LW breeds were identified. These findings offer valuable insights into the genetic underpinnings of skeletal muscle development and present opportunities for enhancing meat production through pig breeding.
Topics: Animals; Polymorphism, Single Nucleotide; Muscle, Skeletal; Swine; Gene Frequency; Muscle Development; Whole Genome Sequencing; Tibet; Genome
PubMed: 38862895
DOI: 10.1186/s12864-024-10508-7 -
NPJ Microgravity Jun 2024Skeletal muscles overcome terrestrial, gravitational loading by producing tensile forces that produce movement through joint rotation. Conversely, the microgravity of...
Skeletal muscles overcome terrestrial, gravitational loading by producing tensile forces that produce movement through joint rotation. Conversely, the microgravity of spaceflight reduces tensile loads in working skeletal muscles, causing an adaptive muscle atrophy. Unfortunately, the design of stable, physiological bioreactors to model skeletal muscle tensile loading during spaceflight experiments remains challenging. Here, we tested a bioreactor that uses initiation and cessation of cyclic, tensile strain to induce hypertrophy and atrophy, respectively, in murine lineage (C2C12) skeletal muscle myotubes. Uniaxial cyclic stretch of myotubes was conducted using a StrexCell® (STB-1400) stepper motor system (0.75 Hz, 12% strain, 60 min day^-1). Myotube groups were assigned as follows: (a) quiescent over 2- or (b) 5-day (no stretch), (c) experienced 2-days (2dHY) or (d) 5-days (5dHY) of cyclic stretch, or (e) 2-days of cyclic stretch followed by a 3-day cessation of stretch (3dAT). Using ß-sarcoglycan as a sarcolemmal marker, mean myotube diameter increased significantly following 2dAT (51%) and 5dAT (94%) vs. matched controls. The hypertrophic, anabolic markers talin and Akt phosphorylation (Thr308) were elevated with 2dHY but not in 3dAT myotubes. Inflammatory, catabolic markers IL-1ß, IL6, and NF-kappaB p65 subunit were significantly higher in the 3dAT group vs. all other groups. The ratio of phosphorylated FoxO3a/total FoxO3a was significantly lower in 3dAT than in the 2dHY group, consistent with elevated catabolic signaling during unloading. In summary, we demonstrated proof-of-concept for a spaceflight research bioreactor, using uniaxial cyclic stretch to produce myotube hypertrophy with increased tensile loading, and myotube atrophy with subsequent cessation of stretch.
PubMed: 38862543
DOI: 10.1038/s41526-023-00320-0 -
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