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Journal of the American Heart... Apr 2023Background Pathological cardiac hypertrophy is regarded as a critical precursor and independent risk factor of heart failure, and its inhibition prevents the progression...
Background Pathological cardiac hypertrophy is regarded as a critical precursor and independent risk factor of heart failure, and its inhibition prevents the progression of heart failure. Switch-associated protein 70 (SWAP70) is confirmed important in immunoregulation, cell maturation, and cell transformation. However, its role in pathological cardiac hypertrophy remains unclear. Methods and Results The effects of SWAP70 on pathological cardiac hypertrophy were investigated in knockout mice and overexpression/knockdown cardiomyocytes. Bioinformatic analysis combined with multiple molecular biological methodologies were adopted to elucidate the mechanisms underlying the effects of SWAP70 on pathological cardiac hypertrophy. Results showed that SWAP70 protein levels were significantly increased in failing human heart tissues, experimental transverse aortic constriction-induced mouse hypertrophic hearts, and phenylephrine-stimulated isolated primary cardiomyocytes. Intriguingly, phenylephrine treatment decreased the lysosomal degradation of SWAP70 by disrupting the interaction of SWAP70 with granulin precursor. In vitro and in vivo experiments revealed that knockdown/knockout accelerated the progression of pathological cardiac hypertrophy, while overexpression restrained the cardiomyocyte hypertrophy. SWAP70 restrained the binding of transforming growth factor β-activated kinase 1 (TAK1) and TAK1 binding protein 1, thus blocking the phosphorylation of TAK1 and downstream c-Jun N-terminal kinase/P38 signaling. TAK1 interacted with the N-terminals (1-192) of SWAP70. (193-585) overexpression failed to inhibit cardiac hypertrophy when the TAK1-SWAP70 interaction was disrupted. Either inhibiting the phosphorylation or suppressing the expression of TAK1 rescued the exaggerated cardiac hypertrophy induced by knockdown. Conclusions SWAP70 suppressed the progression of cardiac hypertrophy, possibly by inhibiting the mitogen-activated protein kinases signaling pathway in a TAK1-dependent manner, and lysosomes are involved in the regulation of SWAP70 expression level.
Topics: Animals; Humans; Mice; Cardiomegaly; DNA-Binding Proteins; Guanine Nucleotide Exchange Factors; Heart Failure; Mice, Knockout; Minor Histocompatibility Antigens; Myocytes, Cardiac; Nuclear Proteins; Phenylephrine; Signal Transduction
PubMed: 36974751
DOI: 10.1161/JAHA.122.028628 -
The Journal of Biological Chemistry Mar 2023The dynamic cycling of O-linked GlcNAc (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes...
The dynamic cycling of O-linked GlcNAc (O-GlcNAc) on and off Ser/Thr residues of intracellular proteins, termed O-GlcNAcylation, is mediated by the conserved enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase. O-GlcNAc cycling is important in homeostatic and stress responses, and its perturbation sensitizes the heart to ischemic and other injuries. Despite considerable progress, many molecular pathways impacted by O-GlcNAcylation in the heart remain unclear. The mitogen-activated protein kinase (MAPK) pathway is a central signaling cascade that coordinates developmental, physiological, and pathological responses in the heart. The developmental or adaptive arm of MAPK signaling is primarily mediated by Erk kinases, while the pathophysiologic arm is mediated by p38 and Jnk kinases. Here, we examine whether O-GlcNAcylation affects MAPK signaling in cardiac myocytes, focusing on Erk1/2 and p38 in basal and hypertrophic conditions induced by phenylephrine. Using metabolic labeling of glycans coupled with alkyne-azide "click" chemistry, we found that Erk1/2 and p38 are O-GlcNAcylated. Supporting the regulation of p38 by O-GlcNAcylation, the OGT inhibitor, OSMI-1, triggers the phosphorylation of p38, an event that involves the NOX2-Ask1-MKK3/6 signaling axis and also the noncanonical activator Tab1. Additionally, OGT inhibition blocks the phenylephrine-induced phosphorylation of Erk1/2. Consistent with perturbed MAPK signaling, OSMI-1-treated cardiomyocytes have a blunted hypertrophic response to phenylephrine, decreased expression of cTnT (key component of the contractile apparatus), and increased expression of maladaptive natriuretic factors Anp and Bnp. Collectively, these studies highlight new roles for O-GlcNAcylation in maintaining a balanced activity of Erk1/2 and p38 MAPKs during hypertrophic growth responses in cardiomyocytes.
Topics: Humans; Myocytes, Cardiac; Signal Transduction; Phosphorylation; Hypertrophy; Proteins; N-Acetylglucosaminyltransferases; Acetylglucosamine
PubMed: 36642184
DOI: 10.1016/j.jbc.2023.102907 -
American Journal of Physiology.... Jan 2022Macrophages are one of the top players when considering immune cells involved with tissue homeostasis. Recently, increasing evidence has demonstrated that macrophages... (Review)
Review
Macrophages are one of the top players when considering immune cells involved with tissue homeostasis. Recently, increasing evidence has demonstrated that macrophages could also present two major subsets during tissue healing: proliferative macrophages (M1-like), which are responsible for increasing myogenic cell proliferation, and restorative macrophages (M2-like), which are involved in the end of the mature muscle myogenesis. The participation and characterization of these macrophage subsets are critical during myogenesis to understand the inflammatory role of macrophages during muscle recovery and to create supportive strategies that can improve mass muscle maintenance. Indeed, most of our knowledge about macrophage subsets comes from skeletal muscle damage protocols, and we still do not know how these subsets can contribute to skeletal muscle adaptation. Thus, this narrative review aims to collect and discuss studies demonstrating the involvement of different macrophage subsets during the skeletal muscle damage/regeneration process, showcasing an essential role of these macrophage subsets during muscle adaptation induced by acute and chronic exercise programs.
Topics: Animals; Cell Proliferation; Exercise; Humans; Hypertrophy; Inflammation; Inflammation Mediators; Macrophages; Muscle, Skeletal; Phenotype; Regeneration; Signal Transduction; Skeletal Muscle Enlargement
PubMed: 34786967
DOI: 10.1152/ajpregu.00038.2021 -
Journal of Applied Physiology... Aug 2019Skeletal muscle mass responds in a remarkable manner to alterations in loading and use. It has long been clear that skeletal muscle hypertrophy can be prevented by... (Review)
Review
Skeletal muscle mass responds in a remarkable manner to alterations in loading and use. It has long been clear that skeletal muscle hypertrophy can be prevented by inhibiting RNA synthesis. Since 80% of the cell's total RNA has been estimated to be rRNA, this finding indicates that de novo production of rRNA via transcription of the corresponding genes is important for such hypertrophy to occur. Transcription of rDNA by RNA Pol I is the rate-limiting step in ribosome biogenesis, indicating in turn that this biogenesis strongly influences the hypertrophic response. The present minireview focuses on ) a brief description of the key steps in ribosome biogenesis and the relationship of this process to skeletal muscle mass and ) the coordination of ribosome biogenesis and protein synthesis for growth or atrophy, as exemplified by the intracellular AMPK and mTOR pathways.
Topics: Animals; Humans; Hypertrophy; Muscle, Skeletal; Muscular Diseases; Protein Biosynthesis; RNA, Ribosomal; Ribosomes; Transcription, Genetic
PubMed: 31219775
DOI: 10.1152/japplphysiol.00963.2018 -
Physiological Research Aug 2023G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has...
G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated. As it has been reported that the lactate administration induces muscle hypertrophy, the stimulation of GPR81 has been suggested to mediate muscle hypertrophy. To clarify the contribution of GPR81 activation in skeletal muscle hypertrophy, in the present study, we investigated the effect of GPR81 agonist administration on skeletal muscle mass in mice. Male C57BL/6J mice were randomly divided into control group and GPR81 agonist-administered group that received oral administration of the specific GPR81 agonist 3-Chloro-5-hydroxybenzoic acid (CHBA). In both fast-twitch plantaris and slow-twitch soleus muscles of mice, the protein expression of GPR81 was observed. Oral administration of CHBA to mice significantly increased absolute muscle weight and muscle weight relative to body weight in the two muscles. Moreover, both absolute and relative muscle protein content in the two muscles were significantly increased by CHBA administration. CHBA administration also significantly upregulated the phosphorylation level of p42/44 extracellular signal-regulated kinase-1/2 (ERK1/2) and p90 ribosomal S6 kinase (p90RSK). These observations suggest that activation of GRP81 stimulates increased the mass of two types of skeletal muscle in mice in vivo. Lactate receptor GPR81 may positively affect skeletal muscle mass through activation of ERK pathway.
Topics: Mice; Male; Animals; Lactic Acid; Mice, Inbred C57BL; Muscle, Skeletal; Muscle Fibers, Skeletal; Receptors, G-Protein-Coupled; Hypertrophy
PubMed: 37795889
DOI: 10.33549/physiolres.935004 -
Cardiovascular Journal of AfricaWe aimed to evaluate and compare papillary muscle free strain in hypertrophic cardiomyopathy (HCMP) and hypertensive (HT) patients.
OBJECTIVES
We aimed to evaluate and compare papillary muscle free strain in hypertrophic cardiomyopathy (HCMP) and hypertensive (HT) patients.
METHODS
Global longitudinal strain (GLS), and longitudinal myocardial strain of the anterolateral (ALPM) and posteromedial papillary muscles (PMPM) were obtained in 46 HCMP and 50 HT patients.
RESULTS
Interventricular septum (IVS)/posterior wall (PW) thickness ratio, left ventricular mass index (LVMI), left atrial anteroposterior diameter (LAAP) and mitral E/E' were found to be increased in patients with HCMP compared to HT patients. Left ventricular cavity dimensions were smaller in HCMP patients. GLS of HCMP and HT patients were - 14.52 ± 3.01 and -16.85 ± 1.36%, respectively ( < 0.001). Likewise, ALPM and PMPM free strain values were significantly reduced in HCMP patients over HT patients [-14.00% (-22 to -11%) and -15.5% (-24.02 to -10.16%) vs -23.00% (-24.99 to -19.01%) and -22.30% (-26.48 to -15.95%) ( = 0.016 and = 0.010)], respectively. ALPM free strain showed a statistically significant correlation with GLS, maximal wall thickness, IVS thickness and LVMI. PMPM free strain showed a significant correlation with GLS, IVS thickness and LAAP. The GLS value of - 13.05 had a sensitivity of 61.9% and a specificity of 97.4% for predicting HCMP. ALPM and PMPM free strain values of -15.31 and -17.17% had 63 and 76.9% sensitivity and 85.7 and 76.9% specificity for prediction of HCMP.
CONCLUSIONS
Besides other echocardiographic variables, which were investigated in earlier studies, papillary muscle free strain also could be used in HCMP to distinguish HCMP- from HT-associated hypertrophy.
Topics: Humans; Hypertrophy, Left Ventricular; Papillary Muscles; Myocardial Contraction; Cardiomyopathy, Hypertrophic; Hypertension; Ventricular Function, Left
PubMed: 36947167
DOI: 10.5830/CVJA-2022-070 -
Cells Aug 2022Improvements in growth-related traits reduce fish time and production costs to reach market size. Feed deprivation and refeeding cycles have been introduced to maximize...
Improvements in growth-related traits reduce fish time and production costs to reach market size. Feed deprivation and refeeding cycles have been introduced to maximize aquaculture profits through compensatory growth. However, the molecular compensatory growth signature is still uncertain in Nile tilapia. In this study, fish were subjected to two weeks of fasting followed by two weeks of refeeding. The growth curve in refed tilapia was suggestive of a partial compensatory response. Transcriptome profiling of starved and refed fish was conducted to identify genes regulating muscle atrophy and compensatory growth. Pairwise comparisons revealed 5009 and 478 differentially expressed (differential) transcripts during muscle atrophy and recovery, respectively. Muscle atrophy appears to be mediated by the ubiquitin-proteasome and autophagy/lysosome systems. Autophagy-related 2A, F-box and WD repeat domain containing 7, F-box only protein 32, miR-137, and miR-153 showed exceptional high expression suggesting them as master regulators of muscle atrophy. On the other hand, the muscle compensatory growth response appears to be mediated by the continuous stimulation of muscle hypertrophy which exceeded normal levels found in control fish. For instance, genes promoting ribosome biogenesis or enhancing the efficiency of translational machinery were upregulated in compensatory muscle growth. Additionally, myogenic microRNAs (e.g., miR-1 and miR-206), and hypertrophy-associated microRNAs (e.g., miR-27a-3p, miR-29c, and miR-29c) were reciprocally expressed to favor hypertrophy during muscle recovery. Overall, the present study provided insights into the molecular mechanisms regulating muscle mass in fish. The study pinpoints extensive growth-related gene networks that could be used to inform breeding programs and also serve as valuable genomic resources for future mechanistic studies.
Topics: Animals; Cichlids; Hypertrophy; MicroRNAs; Muscle, Skeletal; Muscular Atrophy
PubMed: 36010581
DOI: 10.3390/cells11162504 -
The Journal of Clinical Investigation May 2024One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means...
One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means of treating cardiac hypertrophy, although system-wide side effects are common. Regulators of translation, such as cardiac-specific long noncoding RNAs (lncRNAs), could provide new, more targeted therapeutic approaches to inhibit cardiac hypertrophy. Therefore, we generated mice lacking a previously identified lncRNA named CARDINAL to examine its cardiac function. We demonstrate that CARDINAL is a cardiac-specific, ribosome-associated lncRNA and show that its expression was induced in the heart upon pathological cardiac hypertrophy and that its deletion in mice exacerbated stress-induced cardiac hypertrophy and augmented protein translation. In contrast, overexpression of CARDINAL attenuated cardiac hypertrophy in vivo and in vitro and suppressed hypertrophy-induced protein translation. Mechanistically, CARDINAL interacted with developmentally regulated GTP-binding protein 1 (DRG1) and blocked its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 was downregulated, thereby modulating the rate of protein translation in the heart in response to stress. This study provides evidence for the therapeutic potential of targeting cardiac-specific lncRNAs to suppress disease-induced translational changes and to treat cardiac hypertrophy and heart failure.
Topics: Animals; RNA, Long Noncoding; Mice; Cardiomegaly; Protein Biosynthesis; Humans; Mice, Knockout; GTP-Binding Proteins; Myocytes, Cardiac
PubMed: 38743498
DOI: 10.1172/JCI169112 -
Scientific Reports Mar 2023A systematic review and meta-analysis was conducted to determine the effects of resistance training under hypoxic conditions (RTH) on muscle hypertrophy and strength... (Meta-Analysis)
Meta-Analysis
A systematic review and meta-analysis was conducted to determine the effects of resistance training under hypoxic conditions (RTH) on muscle hypertrophy and strength development. Searches of PubMed-Medline, Web of Science, Sport Discus and the Cochrane Library were conducted comparing the effect of RTH versus normoxia (RTN) on muscle hypertrophy (cross sectional area (CSA), lean mass and muscle thickness) and strength development [1-repetition maximum (1RM)]. An overall meta-analysis and subanalyses of training load (low, moderate or high), inter-set rest interval (short, moderate or long) and severity of hypoxia (moderate or high) were conducted to explore the effects on RTH outcomes. Seventeen studies met inclusion criteria. The overall analyses showed similar improvements in CSA (SMD [CIs] = 0.17 [- 0.07; 0.42]) and 1RM (SMD = 0.13 [0.0; 0.27]) between RTH and RTN. Subanalyses indicated a medium effect on CSA for longer inter-set rest intervals and a small effect for moderate hypoxia and moderate loads favoring RTH. Moreover, a moderate effect for longer inter-set rest intervals and a trivial effect for severe hypoxia and moderate loads favoring RTH was found on 1RM. Evidence suggests that RTH employed with moderate loads (60-80% 1RM) and longer inter-set rest intervals (≥ 120 s) enhances muscle hypertrophy and strength compared to normoxia. The use of moderate hypoxia (14.3-16% FiO) seems to be somewhat beneficial to hypertrophy but not strength. Further research is required with greater standardization of protocols to draw stronger conclusions on the topic.
Topics: Humans; Animals; Resistance Training; Gastropoda; Hypertrophy; Hypoxia; Muscles
PubMed: 36871095
DOI: 10.1038/s41598-023-30808-4 -
Basic Research in Cardiology May 2023SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated...
SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury.
Topics: Animals; Mice; Cardiomegaly; Mitochondria; Muscle, Skeletal; Myocytes, Cardiac
PubMed: 37212935
DOI: 10.1007/s00395-023-00991-6