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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 -
FASEB Journal : Official Publication of... Jun 2024Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause...
Female carriers of a Duchenne muscular dystrophy (DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in female mdx mice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in female mdx mice reduces exercise capacity, tricarboxylic acid cycle intermediates, and citrate synthase activity but that these deficits are offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA-binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggest that estrogen mitigates dystrophinopathic features in female mdx mice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.
Topics: Animals; Female; Mice, Inbred mdx; Mice; Estrogens; RNA-Binding Proteins; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Mice, Inbred C57BL; Ovariectomy; Mitochondria; Mitochondria, Muscle
PubMed: 38847487
DOI: 10.1096/fj.202400329R -
ELife Jun 2024Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2...
Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2 is specifically expressed in vertebrate striated muscles. By gene knockdown in zebrafish or genetic knockout in mice, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with being deleted in mature myofibers to assess its role in sarcomere maintenance, and the other in adult muscle satellite cells (MuSCs) to assess its role in de novo sarcomere assembly. We find that Styxl2 is not required for sarcomere maintenance but functions in de novo sarcomere assembly during injury-induced muscle regeneration. Mechanistically, Styxl2 interacts with non-muscle myosin IIs, enhances their ubiquitination, and targets them for autophagy-dependent degradation. Without Styxl2, the degradation of non-muscle myosin IIs is delayed, which leads to defective sarcomere assembly and force generation. Thus, Styxl2 promotes de novo sarcomere assembly by interacting with non-muscle myosin IIs and facilitating their autophagic degradation.
Topics: Animals; Mice; Mice, Knockout; Proteolysis; Sarcomeres; Zebrafish; Phosphoprotein Phosphatases
PubMed: 38829202
DOI: 10.7554/eLife.87434 -
Sports Medicine (Auckland, N.Z.) May 2024The mechanisms underlying range of motion enhancements via flexibility training discussed in the literature show high heterogeneity in research methodology and study... (Review)
Review
The mechanisms underlying range of motion enhancements via flexibility training discussed in the literature show high heterogeneity in research methodology and study findings. In addition, scientific conclusions are mostly based on functional observations while studies considering the underlying physiology are less common. However, understanding the underlying mechanisms that contribute to an improved range of motion through stretching is crucial for conducting comparable studies with sound designs, optimising training routines and accurately interpreting resulting outcomes. While there seems to be no evidence to attribute acute range of motion increases as well as changes in muscle and tendon stiffness and pain perception specifically to stretching or foam rolling, the role of general warm-up effects is discussed in this paper. Additionally, the role of mechanical tension applied to greater muscle lengths for range of motion improvement will be discussed. Thus, it is suggested that physical training stressors can be seen as external stimuli that control gene expression via the targeted stimulation of transcription factors, leading to structural adaptations due to enhanced protein synthesis. Hence, the possible role of serial sarcomerogenesis in altering pain perception, reducing muscle stiffness and passive torque, or changes in the optimal joint angle for force development is considered as well as alternative interventions with a potential impact on anabolic pathways. As there are limited possibilities to directly measure serial sarcomere number, longitudinal muscle hypertrophy remains without direct evidence. The available literature does not demonstrate the necessity of only using specific flexibility training routines such as stretching to enhance acute or chronic range of motion.
PubMed: 38819597
DOI: 10.1007/s40279-024-02043-y -
Cureus May 2024A 37-year-old male with type two diabetes presented to the hospital with new-onset heart failure and renal dysfunction. His left ventricular (LV) ejection fraction was...
A 37-year-old male with type two diabetes presented to the hospital with new-onset heart failure and renal dysfunction. His left ventricular (LV) ejection fraction was less than 10%. Transthoracic echocardiography and cardiovascular magnetic resonance (CMR) imaging also revealed severe bicuspid aortic valve stenosis, dilated cardiomyopathy with LV hypertrophy, prominent LV trabeculations, and features suggestive of mild myocarditis with active inflammation. While myocarditis was suspected on CMR imaging, his mild degree of myocardial involvement did not explain the entirety of his clinical presentation, degree of LV dysfunction, or other structural abnormalities. An extensive work-up for his LV dysfunction was unremarkable for ischemic, metabolic, infiltrative, infectious, toxic, oncologic, connective tissue, and autoimmune etiologies. Genetic testing was positive for a () variant, which was deemed likely to be a unifying etiology underlying his presentation. The sarcomere gene allows beta-myosin expression in heart ventricles, with variants associated with hypertrophic and dilated cardiomyopathies, congenital heart diseases, myocarditis, and excessive trabeculation (formerly known as left ventricular noncompaction). This case highlights the diverse array of cardiac pathologies that can present with gene variants and reviews an extensive work-up for this unusual presentation of heart failure in a young patient.
PubMed: 38813076
DOI: 10.7759/cureus.61252 -
Molecular Biology of the Cell Jul 2024undergo age-dependent declines in muscle organization and function, similar to human sarcopenia. The chaperone UNC-45 is required to fold myosin heads after translation...
undergo age-dependent declines in muscle organization and function, similar to human sarcopenia. The chaperone UNC-45 is required to fold myosin heads after translation and is likely used for refolding after thermally- or chemically-induced unfolding. UNC-45's TPR region binds HSP-90 and its UCS domain binds myosin heads. We observe early onset sarcopenia when UNC-45 is reduced at the beginning of adulthood. There is sequential decline of HSP-90, UNC-45, and MHC B myosin. A mutation in delays sarcopenia and loss of HSP-90, UNC-45, and myosin. UNC-45 undergoes age-dependent phosphorylation, and mass spectrometry reveals phosphorylation of six serines and two threonines, seven of which occur in the UCS domain. Additional expression of UNC-45 results in maintenance of MHC B myosin and suppression of A-band disorganization in old animals. Our results suggest that increased expression or activity of UNC-45 might be a strategy for prevention or treatment of sarcopenia.
Topics: Animals; Caenorhabditis elegans Proteins; Caenorhabditis elegans; Aging; Molecular Chaperones; Myosins; Sarcomeres; Phosphorylation; HSP90 Heat-Shock Proteins; Humans; Mutation; Muscle, Skeletal
PubMed: 38809582
DOI: 10.1091/mbc.E23-12-0488 -
Biophysical Journal May 2024The length-dependent activation (LDA) of maximum force and calcium sensitivity are established features of cardiac muscle contraction but the dominant underlying...
The length-dependent activation (LDA) of maximum force and calcium sensitivity are established features of cardiac muscle contraction but the dominant underlying mechanisms remain to be fully clarified. Alongside the well-documented regulation of contraction via the thin filaments, experiments have identified an additional force-dependent thick-filament activation, whereby myosin heads parked in a so-called off state become available to generate force. This process produces a feedback effect that may potentially drive LDA. Using biomechanical modeling of a human left-ventricular myocyte, this study investigates the extent to which the off-state dynamics could, by itself, plausibly account for LDA, depending on the specific mathematical formulation of the feedback. We hypothesized four different models of the off-state regulatory feedback based on (A) total force, (B) active force, (C) sarcomere strain, and (D) passive force. We tested if these models could reproduce the isometric steady-state and dynamic LDA features predicted by an earlier published model of a human left-ventricle myocyte featuring purely phenomenological length dependences. The results suggest that only total-force feedback (A) is capable of reproducing the expected behaviors, but that passive tension could provide a length-dependent signal on which to initiate the feedback. Furthermore, by attributing LDA to off-state dynamics, our proposed model also qualitatively reproduces experimentally observed effects of the off-state-stabilizing drug mavacamten. Taken together, these results support off-state dynamics as a plausible primary mechanism underlying LDA.
PubMed: 38807364
DOI: 10.1016/j.bpj.2024.05.025 -
Heart and Vessels May 2024Hypertrophic cardiomyopathy (HCM) patients with sarcomere mutations have an increased risk of heart failure and left ventricular (LV) systolic dysfunction. We...
Hypertrophic cardiomyopathy (HCM) patients with sarcomere mutations have an increased risk of heart failure and left ventricular (LV) systolic dysfunction. We hypothesize that sarcomere mutation carriers have abnormal myocardial contractility before LV dysfunction. Therefore, we aimed to associate myocardial contractility with identified sarcomere mutations and predict genotyped HCM patients with sarcomere mutation by three-dimensional speckle tracking imaging (3D-STI). A retrospective analysis of 117 HCM patients identified 32 genotype-positive (G +) and 85 genotype-negative (G-) patients. Genotype-positive patients had higher globe circumferential strain (GCS), globe longitudinal strain (GLS), and globe radial strain (GRS) (p < 0.05), and multivariate logistic regression revealed that these variables were associated with a positive genetic status (p < 0.05). After the propensity matches other possible influencing factors, we developed three models, named Model GCS, Model GLS, and Model GRS, which could identified genotype-positive HCM patients with excellent performance (AUC of 0.855, 0.833, and 0.870 respectively, all p < 0.001). Genotype-positive HCM patients show a higher myocardial hyper-contractility status than patients without sarcomere mutations. When combined with clinical and echocardiographic markers, the 3D-STI parameters can effectively identify the likelihood of genotype-positive HCM.
PubMed: 38806839
DOI: 10.1007/s00380-024-02414-5 -
Circulation. Genomic and Precision... Jun 2024Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Substantial data support a heritable basis for supraventricular tachycardias, but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood. We sought to identify genetic loci associated with atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular accessory pathways or atrioventricular reciprocating tachycardia (AVAPs/AVRT).
METHODS
We performed multiancestry meta-analyses of genome-wide association studies to identify genetic loci for AVNRT (4 studies) and AVAP/AVRT (7 studies). We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and examining prior genome-wide association studies.
RESULTS
Analyses comprised 2384 AVNRT cases and 106 489 referents, and 2811 AVAP/AVRT cases and 1,483 093 referents. We identified 2 significant loci for AVNRT, which implicate and as disease susceptibility genes. A transcriptome-wide association analysis supported an association between reduced predicted cardiac expression of and AVNRT. We identified 3 significant loci for AVAP/AVRT, which implicate , , and . Variant associations at several loci have been previously reported for cardiac phenotypes, including atrial fibrillation, stroke, Brugada syndrome, and electrocardiographic intervals.
CONCLUSIONS
Our findings highlight gene regions associated with ion channel function (AVAP/AVRT), as well as cardiac development and the sarcomere (AVAP/AVRT and AVNRT) as important potential effectors of supraventricular tachycardia susceptibility.
Topics: Humans; Genome-Wide Association Study; Tachycardia, Supraventricular; Genetic Predisposition to Disease; Tachycardia, Atrioventricular Nodal Reentry; Polymorphism, Single Nucleotide; Connectin; Transcriptome
PubMed: 38804128
DOI: 10.1161/CIRCGEN.123.004320