-
Frontiers in Cardiovascular Medicine 2024The kynurenine pathway (KP) serves as the primary route for tryptophan metabolism in most mammalian organisms, with its downstream metabolites actively involved in... (Review)
Review
The kynurenine pathway (KP) serves as the primary route for tryptophan metabolism in most mammalian organisms, with its downstream metabolites actively involved in various physiological and pathological processes. Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) serve as the initial and pivotal enzymes of the KP, with IDO playing important and intricate roles in cardiovascular diseases. Multiple metabolites of KP have been observed to exhibit elevated concentrations in plasma across various cardiovascular diseases, such as atherosclerosis, hypertension, and acute myocardial infarction. Multiple studies have indicated that kynurenine (KYN) may serve as a potential biomarker for several adverse cardiovascular events. Furthermore, Kynurenine and its downstream metabolites have complex roles in inflammation, exhibiting both inhibitory and stimulatory effects on inflammatory responses under different conditions. In atherosclerosis, upregulation of IDO stimulates KYN production, mediating aromatic hydrocarbon receptor (AhR)-induced exacerbation of vascular inflammation and promotion of foam cell formation. Conversely, in arterial calcification, this mediation alleviates osteogenic differentiation of vascular smooth muscle cells. Additionally, in cardiac remodeling, KYN-mediated AhR activation exacerbates pathological left ventricular hypertrophy and fibrosis. Interventions targeting components of the KP, such as IDO inhibitors, 3-hydroxyanthranilic acid, and anthranilic acid, demonstrate cardiovascular protective effects. This review outlines the mechanistic roles of KP in coronary atherosclerosis, arterial calcification, and myocardial diseases, highlighting the potential diagnostic, prognostic, and therapeutic value of KP in cardiovascular diseases, thus providing novel insights for the development and application of related drugs in future research.
PubMed: 38883986
DOI: 10.3389/fcvm.2024.1406856 -
Physiological Genomics Jun 2024To investigate inter-individual differences in muscle thickness of Rectus Femoris (MTRF) following 12 weeks of Resistance Training (RT) or High-Intensity Interval...
To investigate inter-individual differences in muscle thickness of Rectus Femoris (MTRF) following 12 weeks of Resistance Training (RT) or High-Intensity Interval Training (HIIT) to explore the genetic architecture underlying skeletal muscle hypertrophy and to construct predictive models. We conducted musculoskeletal ultrasound assessments of the MTRF response in 440 physically inactive adults after the 12-week exercise period. A Genome-wide Association study (GWAS) was employed to identify variants associated with MTRF response, separately for RT and HIIT. Utilizing polygenic predictor score (PPS), we estimated the genetic contribution to exercise-induced hypertrophy. Predictive models for MTRF response were constructed using Random Forest (RF), Support Vector Mac (SVM), and Generalized Linear Model (GLM) in 10 cross-validated approach. MTRF increased significantly after both RT (8.8%, P<0.05) and HIIT (5.3%, P<0.05), but with considerable inter-individual differences (RT: -13.5~38.4%, HIIT: -14.2%~30.7%). Eleven lead SNPs in RT and eight lead SNPs in HIIT were identified at a significance level of P<1×10. The PPS was associated with MTRF response, explaining 47.2% of the variation in response to RT and 38.3% of the variation in response to HIIT. Notably, the GLM and SVM predictive models exhibited superior performance in comparison to RF models (p<0.05), and the GLM demonstrated optimal performance with an AUC of 0.809 (95%CI:0.669-0.949). Factors such as PPS, baseline MTRF, and exercise protocol exerted influence on the MTRF response to exercise, with PPS being the primary contributor. The GLM and SVM predictive model, incorporating both genetic and phenotypic factors, emerged as promising tools for predicting exercise-induced skeletal muscle hypertrophy.
PubMed: 38881426
DOI: 10.1152/physiolgenomics.00019.2024 -
Trends in Molecular Medicine Jun 2024A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or... (Review)
Review
A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or aging muscle could be detrimental, since muscular weakness is inversely associated with all-cause mortality. Sarcopenia is characterized by a decline in skeletal muscle mass and strength and is associated with aging. Exercise is the only effective therapy to delay sarcopenia development and improve muscle health in older adults. Although numerous interventions have been proposed to reduce sarcopenia, none has yet succeeded in clinical trials. This review evaluates the biological gap between recent clinical trials targeting sarcopenia and the preclinical studies on which they are based, and suggests an alternative approach to bridge the discrepancy.
PubMed: 38880726
DOI: 10.1016/j.molmed.2024.05.016 -
Journal of Pharmacological Sciences Aug 2024The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart...
The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart failure, as well as interstitial fibrosis. Conversely, myocardial hypertrophy resulting from hemodynamic loading is perceived as compensatory stress adaptation. We previously reported the abundant presence of highly redox-active polysulfide molecules, termed supersulfide, with two or more sulfur atoms catenated in normal hearts, and the supersulfide catabolism in pathologic hearts after myocardial infarction correlated with worsened prognosis of heart failure. However, the impact of supersulfide on myocardial remodeling remains unclear. Here, we investigated the involvement of supersulfide metabolism in cardiomyocyte remodeling, using a model of adenosine 5'-triphosphate (ATP) receptor-stimulated atrophy and endothelin-1 receptor-stimulated hypertrophy in neonatal rat cardiomyocytes. Results revealed contrasting changes in intracellular supersulfide and its catabolite, hydrogen sulfide (HS), between cardiomyocyte atrophy and hypertrophy. Stimulation of cardiomyocytes with ATP decreased supersulfide activity, while HS accumulation itself did not affect cardiomyocyte atrophy. This supersulfide catabolism was also involved in myofibroblast formation of neonatal rat cardiac fibroblasts. Thus, unraveling supersulfide metabolism during myocardial remodeling may lead to the development of novel therapeutic strategies to improve heart failure.
Topics: Animals; Myocytes, Cardiac; Sulfides; Hydrogen Sulfide; Cells, Cultured; Ventricular Remodeling; Adenosine Triphosphate; Rats; Atrophy; Cardiomegaly; Heart Failure; Animals, Newborn; Rats, Sprague-Dawley
PubMed: 38880546
DOI: 10.1016/j.jphs.2024.05.002 -
Antioxidants & Redox Signaling Jun 2024Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber...
AIMS
Redox signaling plays a key role in skeletal muscle remodeling induced by exercise and prolonged inactivity, but it is unclear which oxidant triggers myofiber hypertrophy due to the lack of strategies to precisely regulate individual oxidants in vivo. In this study, we used tetrathiomolybdate (TM) to dissociate the link between superoxide and H2O2 and thereby to specifically explore the role of superoxide in muscle hypertrophy in C2C12 cells and mice.
RESULTS
TM can linearly regulate intracellular superoxide levels by inhibition of superoxide dismutase 1 (SOD1). A 70% increase in superoxide levels in C2C12 myoblast cells and mice is necessary and sufficient for triggering hypertrophy of differentiated myotubes, and can enhance exercise performance by more than 50% in mice. SOD1 knockout blocks TM-induced superoxide increments and thereby prevents hypertrophy, whereas SOD1 restoration rescues all these effects. Scavenging superoxide with antioxidants abolishes TM-induced hypertrophy and the enhancement of exercise performance, while the restoration of superoxide levels with a superoxide generator promotes muscle hypertrophy independent of SOD1 activity.
INNOVATION AND CONCLUSION
These findings suggest that superoxide is an endogenous initiator of myofiber hypertrophy, and that TM may be used to treat muscle wasting diseases. Our work not only suggests a novel druggable mechanism to increase muscle mass but also provides a tool for precisely regulating superoxide levels in vivo.
PubMed: 38877802
DOI: 10.1089/ars.2024.0595 -
Journal of Bodywork and Movement... Jul 2024The present study aimed to determine the magnitude and intervention time of resistance training required to generate adaptations in the muscle thickness of the... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The present study aimed to determine the magnitude and intervention time of resistance training required to generate adaptations in the muscle thickness of the quadriceps muscle obtained by ultrasound in healthy adults.
METHOD
A systematic review with meta-analysis was conducted on studies recovered from Pubmed, Web of Science, and Scopus databases up to March 2022. The study selection process was carried out by two independent researchers, with the presence of a third researcher in case of disagreements. The methodological quality of the studies was determined with the TESTEX scale, and the risk of bias analysis was determined using Cochrane's RoB 2.0 tool. The meta-analysis used the inverse of the variance with a fixed model, and the effect size was reported by the standardized mean difference (SMD) with a confidence interval of 95%.
RESULTS
Ten studies were included in a meta-analysis. The overall analysis of the studies demonstrated an SMD = 0.35 [95% CI: 0.13-0.56] (P = 0.002), with a low heterogeneity of I = 0% (P = 0.52). No publication bias was detected using a funnel plot followed by Egger's test (P = 0.06). The degree of certainty of the meta-analysis was high using the GRADE tool.
CONCLUSION
We found that resistance training can generate significant average increases of 16.6% in muscle thickness obtained by ultrasound in the quadriceps femoris muscles of healthy adults. However, the subgroup analysis showed that significant effect sizes were only observed after eight weeks of training.
Topics: Humans; Resistance Training; Quadriceps Muscle; Ultrasonography; Muscle Strength
PubMed: 38876638
DOI: 10.1016/j.jbmt.2024.02.007 -
Pharmacological Research Jul 2024Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a...
Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.
Topics: Animals; Heart Failure; Histone-Lysine N-Methyltransferase; Myocytes, Cardiac; Endoplasmic Reticulum Stress; Male; Mice, Inbred C57BL; Humans; Mice, Knockout; Rats; Mice; Cells, Cultured; Cardiomegaly; Rats, Sprague-Dawley; Thrombospondins
PubMed: 38876442
DOI: 10.1016/j.phrs.2024.107263 -
European Journal of Sport Science Jun 2024While significant progress has been made in understanding the resistance training (RT) strategy for muscle hypertrophy increase, there remains limited knowledge about... (Randomized Controlled Trial)
Randomized Controlled Trial
While significant progress has been made in understanding the resistance training (RT) strategy for muscle hypertrophy increase, there remains limited knowledge about its impact on fat mass loss. This study aimed to investigate whether full-body is superior to split-body routine in promoting fat mass loss among well-trained males. Twenty-three participants were randomly assigned to 1 of 2 groups: full-body (n = 11, training muscle groups 5 days per week) and split-body (n = 12, training muscle groups 1 day per week). Both groups performed a weekly set volume-matched condition (75 sets/week, 8-12 repetition maximum at 70%-80 % of 1RM) for 8 weeks, 5 days per week with differences only in the routine. Whole-body and regional fat were assessed using DXA at the beginning and at the end of the study. Full-body RT elicited greater losses compared to split-body in whole-body fat mass (-0.775 ± 1.120 kg vs. +0.317 ± 1.260 kg; p = 0.040), upper-limb fat mass (-0.085 ± 0.118 kg vs. +0.066 ± 0.162 kg; p = 0.019), gynoid fat mass (-0.142 ± 0.230 kg vs. +0.123 ± 0.230 kg; p = 0.012), lower-limb fat mass (-0.197 ± 0.204 kg vs. +0.055 ± 0.328 kg; p = 0.040), and a trend in interaction in android fat mass (-0.116 ± 0.153 kg vs. +0.026 ± 0.174 kg; p = 0.051), with large effects sizes (η ≥ 0.17). This study provides evidence that full-body is more effective in reducing whole-body and regional fat mass compared to split-body routine in well-trained males.
Topics: Humans; Male; Resistance Training; Young Adult; Adult; Body Composition; Adipose Tissue; Muscle, Skeletal; Absorptiometry, Photon
PubMed: 38874955
DOI: 10.1002/ejsc.12104 -
Physiological Reports Jun 2024ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in...
ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology in male mice. Three weeks post-surgery, ERK3, but not ERK4 or p38α, co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3 than TAC-ERK3 hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3 hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and "activated" myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-β-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.
Topics: Animals; Male; Mice; Fibroblasts; Collagen Type I; Collagen Type I, alpha 1 Chain; Myocardium; Mitogen-Activated Protein Kinase 6; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Mitogen-Activated Protein Kinase 3; Cells, Cultured; Cardiomegaly; Myocytes, Cardiac
PubMed: 38872461
DOI: 10.14814/phy2.16108 -
Journal of Medical Economics Jun 2024Patients with obstructive hypertrophic cardiomyopathy (oHCM) experience significant clinical burden which is associated with a high economic burden. Peak oxygen uptake... (Review)
Review
Patients with obstructive hypertrophic cardiomyopathy (oHCM) experience significant clinical burden which is associated with a high economic burden. Peak oxygen uptake (pVO2), measured by cardiopulmonary exercise testing, is used to quantify functional capacity, and has been studied as a primary endpoint in recent clinical trials. This study aimed to gather evidence to consolidate the prognostic value of pVO2 in oHCM and to assess whether it is feasible to predict health outcomes in an economic model based on changes in pVO2. A targeted literature review was conducted in MEDLINE (via PubMed) and Embase databases to identify evidence on the prognostic value of pVO2 as a surrogate health outcome to support future oHCM economic model development. Following screening, study characteristics, population characteristics and pVO2 prognostic association data were extracted. A total of 4,687 studies were identified. 3,531 and 538 studies underwent title/abstract and full-text screening, respectively, of which 151 were included and 9 of these were in hypertrophic cardiomyopathy (HCM); only 3 studies focused on oHCM. The 9 HCM studies consisted of 1 systematic literature review and 8 primary studies reporting on 27 potentially predictive relationships from a pVO2-based metric with clinical outcomes including all-cause mortality, cardiovascular mortality, sudden cardiac death, transplant, paroxysmal and permanent atrial fibrillation. pVO2 was described as a predictor of single and composite endpoints, in 3 and 6 studies respectively, with 1 study reporting on both. This study primarily uses systemic literature review methods but does not qualify as one due to not entailing parallel reviewers during title-abstract and full-text stages of review. The findings of this study suggest pVO2 is predictive of multiple health outcomes, providing rationale to use pVO2 in the development of an economic model.
PubMed: 38868944
DOI: 10.1080/13696998.2024.2367920