Journal of molecular and cellular cardiology最新文献

{"title":"A novel SCN3B in-frame codon deletion in a Brugada syndrome patient: Implications for disrupted NaV1.5 function","authors":"Sahib S. Sarbjit-Singh ,&nbsp;Samir W. Hamaia ,&nbsp;Christopher A. Beaudoin ,&nbsp;Christopher L.-H. Huang ,&nbsp;Greg J. Mellor ,&nbsp;Antony P. Jackson ,&nbsp;Samantha C. Salvage","doi":"10.1016/j.yjmcc.2024.12.011","DOIUrl":"10.1016/j.yjmcc.2024.12.011","url":null,"abstract":"<div><h3>Introduction</h3><div>Brugada Syndrome (BrS) is an inherited arrhythmia syndrome characterised by ST-segment elevation in the right precordial ECG leads and is associated with an increased risk of sudden cardiac death. We identify and characterise a novel SCN3B variant encoding the regulatory β3-subunit of the cardiac voltage-gated sodium channel, Na_V1.5.</div></div><div><h3>Methods and results</h3><div>A 54-year-old Caucasian male presented with palpitations and dizziness. An ECG identified a spontaneous type 1 BrS pattern and review of his medical records revealed a prior type 1 BrS ECG. Next generation sequencing of a BrS risk panel of genes identified a novel SCN3B deletion (c. c412–414, p.T138Del) yielding a single amino acid deletion. No other pathogenic variants were identified. Using site-directed mutagenesis we made the β3-ΔT138 variant and examined structural and functional effects in a heterologous system. Computational predictions together with circular dichroism spectroscopy showed highly localised structural perturbations with minimal effect on the gross protein architecture. Biotinylation, co-immunoprecipitation and surface cross-linking experiments identified normal β3 surface expression and interaction with Na_V1.5. Electrophysiological analysis identified reduced peak current and channel availability. Additionally, an accelerated fast inactivation was observed only in the presence of both wild-type and ΔT138 β3-subunits, reflecting the heterozygous individual. These effects are consistent with a loss-of-function phenotype.</div></div><div><h3>Conclusion</h3><div>A novel BrS associated SCN3B deletion introduced minimally disruptive structural perturbations to the regulatory β3-subunit of Na_V1.5, yet exerted significant electrophysiological effects. This variant highlights nuances of the Na_V1.5-β3 interaction and its role in maintaining normal cardiac excitability.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"200 ","pages":"Pages 11-23"},"PeriodicalIF":4.9,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143006973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TFPI2 hypermethylation promotes diabetic atherosclerosis progression through the Ap2α/PPARγ axis","authors":"Zongyi Xia ,&nbsp;Chi Zhou ,&nbsp;Yefeng Hong ,&nbsp;Fuhai Li ,&nbsp;Wenzhong Zhang ,&nbsp;Hongwei Ji ,&nbsp;Yu Xiao ,&nbsp;Shifang Li ,&nbsp;Shufa Li ,&nbsp;Xiaohong Lu ,&nbsp;Shaohua Li ,&nbsp;Kai Tan ,&nbsp;Hui Xin ,&nbsp;Zhaoyang Wang ,&nbsp;Zhenxun Lian ,&nbsp;Mengqi Guo","doi":"10.1016/j.yjmcc.2024.11.010","DOIUrl":"10.1016/j.yjmcc.2024.11.010","url":null,"abstract":"<div><div>Diabetes mellitus significantly escalates the risk of accelerated atherosclerosis (AS), severely affecting cardiovascular health. Our research, leveraging Gene Expression Omnibus (GEO) database analysis (GSE118481), revealed diminished TFPI2 expression in diabetic patients' atherosclerotic plaques. Further validation in carotid artery plaques and an AS mouse model confirmed TFPI2's reduced expression in diabetes. Through TFPI2 knockdown in non-diabetic mice, we observed aggravated plaque burden and increased inflammatory M1 macrophage polarization. Conversely, TFPI2 overexpression in diabetic mice improved plaque stability and induced reparative M2 macrophage polarization, countering hyperglycemia's negative effects. Mechanistically, transcription factor activator protein 2α (AP-2α) is a repressor of PPPARg transcription, and the interaction of TFPI2 with the transcription factor AP-2α blocks AP-2α binding to the PPARγ gene promoter, which is essential for PPARγ-mediated transcription and the transition from M1 to M2 macrophages. Additionally, hyperglycemia-induced DNA methyltransferase 1 (DNMT1) upregulation heightens TFPI2 methylation, reducing its expression. Our findings spotlight the TFPI2/AP-2α/PPARγ axis as crucial in diabetic AS modulation, proposing its targeting as a new therapeutic strategy to halt diabetes-driven AS progression, highlighting TFPI2's therapeutic promise in addressing diabetes-related cardiovascular issues.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Pages 45-59"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FSTL1 protects against acute aortic dissection by suppressing vascular smooth muscle cell phenotypic switching and degradation of the extracellular matrix","authors":"Jun-ping Li ,&nbsp;Wan-bing He ,&nbsp;Shu-wan Xu ,&nbsp;Juan-zhang Liu ,&nbsp;Zhao-qi Huang ,&nbsp;Chang-ping Li ,&nbsp;Chun-ling Huang ,&nbsp;Pei-biao Mai ,&nbsp;Deng-feng Geng ,&nbsp;Xiao-fu Qiu ,&nbsp;Zhao-yu Liu ,&nbsp;Kun Zhang ,&nbsp;Shu-xian Zhou","doi":"10.1016/j.yjmcc.2024.11.008","DOIUrl":"10.1016/j.yjmcc.2024.11.008","url":null,"abstract":"<div><div>Acute aortic dissection (AAD) is a life-threatening cardiovascular emergency, which is closely related to the vascular smooth muscle cells (VSMCs) phenotypic switching and extracellular matrix (ECM) degradation. Previous studies have found that the secreted extracellular glycoprotein Follistatin-like 1 (FSTL1) is demonstrated as a protective factor for cardiovascular diseases. However, the role of FSTL1 in AAD remains elusive. We aimed to investigate whether FSTL1 could regulate VSMCs phenotypic switching and ECM degradation in AAD. Firstly, we found that FSTL1 expression in aorta was significantly decreased in human AAD examined by western blot and immunohistochemical staining. Then we established a mouse AAD model by administering β-aminopropionitrile (BAPN) dissolved in drinking water for 28 days. We found that FSTL1 expression in aorta was also decreased in mouse AAD. Exogenous supplement with recombinant human FSTL1 protein could rescue VSMCs phenotypic switching and ECM degradation to reduce the occurrence and progression of mouse AAD. <em>In vitro</em>, FSTL1 protein and adenovirus overexpressing FSTL1 (ad-FSTL1) reversed the primary VSMCs phenotypic switching and decreased the expression of MMP2 induced by PDGF-BB. Knocking down FSTL1 initiates VSMCs phenotypic switching and increases the expression of MMP2. In terms of mechanisms, AMPK phosphorylation was decreased and could be improved by FSTL1 protein in mouse AAD. FSTL1 protein and ad-FSTL1 reversed the decreased AMPK phosphorylation induced by PDGF-BB in primary VSMCs. These findings indicate that FSTL1 protects against VSMCs phenotypic switching and ECM degradation in AAD, and targeting FSTL1 may be a potential new strategy for prevention and treatment of AAD.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Pages 60-73"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Congratulations to our Top Papers of 2024","authors":"","doi":"10.1016/S0022-2828(24)00222-0","DOIUrl":"10.1016/S0022-2828(24)00222-0","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Page iii"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143140914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recognizing outstanding reviewers for JMCC in 2024","authors":"","doi":"10.1016/S0022-2828(24)00223-2","DOIUrl":"10.1016/S0022-2828(24)00223-2","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Page iv"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143140915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MMP-2 inhibition attenuates ER stress-mediated cell death during myocardial ischemia-reperfusion injury by preserving IRE1α","authors":"Wesam Bassiouni ,&nbsp;Zabed Mahmud ,&nbsp;Thomas Simmen ,&nbsp;John M. Seubert ,&nbsp;Richard Schulz","doi":"10.1016/j.yjmcc.2024.11.013","DOIUrl":"10.1016/j.yjmcc.2024.11.013","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) stress is one of the major events accompanying myocardial ischemia-reperfusion (IR) injury, as hypoxia and oxidative stress disrupt protein folding in the ER. As a result, the unfolded protein response (UPR) is activated through different sensors including inositol-requiring enzyme 1α (IRE1α) and protein kinase R-like ER kinase (PERK). Failure of the UPR to reduce ER stress induces cellular dysfunction. Matrix metalloproteinase-2 (MMP-2) is a ubiquitous protease that is activated intracellularly in response to oxidative stress and partially localizes near the ER. However, its role in ER homeostasis is unknown. We hypothesized that MMP-2 is involved in the regulation of the UPR and ER stress-mediated apoptosis during IR injury. Isolated mouse hearts subjected to IR injury showed impaired recovery of post-ischemic contractile function compared to aerobically perfused controls. Ventricular extracts from IR hearts had higher levels of glucose-regulated protein-78 and protein disulfide isomerase and lower levels of IRE1α and PERK compared to aerobic controls. MMP-2 inhibitors, ARP-100 or ONO-4817, given 10 min before ischemia, improved cardiac post-ischemic recovery and preserved IRE1α level in hearts subjected to 30 min ischemia/40 min reperfusion. IR also increased the levels of CHOP and mitochondrial Bax and caspase-3 and -9 activities, indicating induction of apoptosis, all of which were attenuated by MMP-2 inhibitors, regardless of the reperfusion time. Immunoprecipitation showed an association between MMP-2 and IRE1α in aerobic and IR hearts. During myocardial IR injury MMP-2 may impair the UPR and induce apoptosis by proteolysis of IRE1α. Inhibition of MMP-2 activity protects against cardiac contractile dysfunction in part by preserving IRE1α and preventing the progression to myocardial cell death.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Pages 74-88"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-specific hiPSC-derived cardiomyocytes indicate allelic and contractile imbalance as pathogenic factor in early-stage Hypertrophic Cardiomyopathy","authors":"Natalie Weber ,&nbsp;Judith Montag ,&nbsp;Kathrin Kowalski ,&nbsp;Bogdan Iorga ,&nbsp;Jeanne de la Roche ,&nbsp;Tim Holler ,&nbsp;Daniel Wojciechowski ,&nbsp;Meike Wendland ,&nbsp;Ante Radocaj ,&nbsp;Anne-Kathrin Mayer ,&nbsp;Anja Brunkhorst ,&nbsp;Felix Osten ,&nbsp;Valentin Burkart ,&nbsp;Birgit Piep ,&nbsp;Alea Bodenschatz ,&nbsp;Pia Gibron ,&nbsp;Kristin Schwanke ,&nbsp;Annika Franke ,&nbsp;Stefan Thiemann ,&nbsp;Anastasia Koroleva ,&nbsp;Theresia Kraft","doi":"10.1016/j.yjmcc.2024.11.007","DOIUrl":"10.1016/j.yjmcc.2024.11.007","url":null,"abstract":"<div><div>Hypertrophic Cardiomyopathy (HCM) is often caused by heterozygous mutations in β-myosin heavy chain (<em>MYH7</em>, β-MyHC). In addition to hyper- or hypocontractile effects of HCM-mutations, heterogeneity in contractile function (<em>contractile imbalance</em>) among individual cardiomyocytes was observed in end-stage HCM-myocardium. <em>Contractile imbalance</em> might be induced by burst-like transcription, leading to unequal fractions of mutant versus wildtype mRNA and protein in individual cardiomyocytes (allelic imbalance). Until now it is not known if allelic and <em>contractile imbalance</em> are present early in HCM-development or rather occur in response to disease-associated remodeling.</div><div>To address this question, we used patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with heterozygous <em>MYH7</em>-mutations R723G and G741R as models of early-stage HCM without secondary adaptions upon disease progression. R723G-hiPSC-CMs showed typical HCM-markers like hypertrophy and myofibrillar disarray. Using RNA-FISH and allele-specific single-cell-PCR, we show for both cell lines that <em>MYH7</em> is transcribed in bursts. Highly variable mutant vs. wildtype <em>MYH7</em>-mRNA fractions in individual HCM-hiPSC-CMs indicated allelic imbalance. HCM-hiPSC-CM-lines showed functional alterations like slowed twitch contraction kinetics and reduced calcium sensitivity of myofibrillar force generation. A significantly larger variability in force generation or twitch parameters of individual HCM-hiPSC-CMs compared to WT-hiPSC-CMs indicated <em>contractile imbalance</em>.</div><div>Our results with early-stage hiPSC-CMs strongly suggest that burst-like transcription and allelic imbalance are general features of CMs, which together with mutation-induced changes of sarcomere contraction could induce <em>contractile imbalance</em> in heterozygous CMs, presumably aggravating development of HCM. Genetic or epigenetic approaches targeting functional heterogeneity in HCM could lead to promising future therapies, in addition to myosin modulation.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Pages 112-125"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of miR-92a normalizes vascular gene expression and prevents diastolic dysfunction in heart failure with preserved ejection fraction","authors":"Badder Kattih ,&nbsp;Ariane Fischer ,&nbsp;Marion Muhly-Reinholz ,&nbsp;Lukas Tombor ,&nbsp;Luka Nicin ,&nbsp;Sebastian Cremer ,&nbsp;Andreas M. Zeiher ,&nbsp;David John ,&nbsp;Wesley Tyler Abplanalp ,&nbsp;Stefanie Dimmeler","doi":"10.1016/j.yjmcc.2024.11.004","DOIUrl":"10.1016/j.yjmcc.2024.11.004","url":null,"abstract":"<div><div>Heart failure with preserved ejection fraction (HFpEF) remains a major public health burden with increasing prevalence but only few effective therapies. Endothelial dysfunction and inflammation are identified as pathophysiological drivers of HFpEF disease progression. MicroRNAs are increasingly recognized as key regulators of these pathological processes, while antimiR-based therapies have been emerged as promising therapeutics in mice and humans. Therefore, we tested whether miR-92a-3p inhibition is a promising therapeutic intervention to target HFpEF in vivo.</div><div>By injection of locked nucleic acid (LNA)-based antimiR (LNA-92a) weekly, we demonstrate that inhibition of miR-92a-3p attenuates the development of diastolic dysfunction and left atrial dilation following experimental induction of HFpEF in mice. Indeed, LNA-92a depleted miR-92a-3p expression in the myocardium and peripheral blood, and derepressed predicted target genes in a cell type-specific manner. Furthermore, cell-type specific efficacy of LNA-92a treatment was assessed by single-nuclear RNA sequencing of HFpEF hearts either treated with LNA-92a or LNA-Control. Endothelial cells of LNA-92a treated mice showed normalized vascular gene expression and reduced gene signatures associated with endothelial-mesenchymal transition.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that LNA-based antimiR-92a is an effective therapeutic strategy to target diastolic dysfunction and left atrial dilation in HFpEF.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Pages 89-98"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142729701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The sodium/glucose cotransporter 2 inhibitor Empagliflozin inhibits long QT 3 late sodium currents in a mutation specific manner","authors":"Lynn C. Lunsonga ,&nbsp;Mohammad Fatehi ,&nbsp;Wentong Long ,&nbsp;Amy J. Barr ,&nbsp;Brittany Gruber ,&nbsp;Arkapravo Chattopadhyay ,&nbsp;Khaled Barakat ,&nbsp;Andrew G. Edwards ,&nbsp;Peter E. Light","doi":"10.1016/j.yjmcc.2024.11.014","DOIUrl":"10.1016/j.yjmcc.2024.11.014","url":null,"abstract":"<div><h3>Background</h3><div>Sodium/glucose cotransporter 2 inhibitors (SGLT2is) like empagliflozin have demonstrated cardioprotective effects in patients with or without diabetes. SGLT2is have been shown to selectively inhibit the late component of cardiac sodium current (late I_Na). Induction of late I_Na is the primary mechanism in the pathophysiology of congenital long QT syndrome type 3 (LQT3) gain-of-function mutations in the SCN5A gene encoding Nav1.5. We investigated empagliflozin's effect on late I_Na in thirteen known LQT3 mutations located in distinct regions of the channel.</div></div><div><h3>Methods</h3><div>The whole-cell patch-clamp technique was used to investigate the effect of empagliflozin on late I_Na in recombinantly expressed Nav1.5 channels containing different LQT3 mutations. Molecular modeling of human Nav1.5 and simulations in a mathematical model of human ventricular myocytes were used to extrapolate our experimental results to excitation-contraction coupling.</div></div><div><h3>Results</h3><div>Empagliflozin selectively inhibited late I_Na in LQT3 mutations in the inactivation gate region of Nav1.5, without affecting peak current or channel kinetics. In contrast, empagliflozin inhibited both peak and late I_Na in mutations in the S4 voltage-sensing regions, altered channel gating, and slowed recovery from inactivation. Empagliflozin had no effect on late/peak I_Na or channel kinetics in channels with mutations in the putative empagliflozin binding region. Simulation results predict that empagliflozin may have a desirable therapeutic effect in LQT3 mutations in the inactivation gate region.</div></div><div><h3>Conclusions</h3><div>Empagliflozin selectively inhibits late I_Na, without affecting channel kinetics, in LQT3 mutations in the inactivation gate region. Empagliflozin may thus be a promising precision medicine approach for patients with specific LQT3 mutations.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Pages 99-111"},"PeriodicalIF":4.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clockwork conditioning: Aligning the skeletal muscle clock with time-of-day exercise for cardiometabolic health","authors":"Spencer B. Procopio,&nbsp;Karyn A. Esser","doi":"10.1016/j.yjmcc.2024.11.011","DOIUrl":"10.1016/j.yjmcc.2024.11.011","url":null,"abstract":"<div><div>Circadian rhythms have evolved to synchronize gene expression, physiology, and behavior with time-of-day changes in the external environment. In every mammalian cell exists a core clock mechanism that consists of a transcriptional-translational feedback loop that drives rhythmic gene expression. Circadian disruption, as observed in shift workers and genetic mouse models, contributes to the onset and progression of cardiometabolic disorders. The central clock, located in the hypothalamus, is uniquely sensitive to external light cues, while the peripheral clocks are responsive to non-photic stimuli such as feeding and activity in addition to signals from the central clock. Recent research has illustrated the sensitivity of the skeletal muscle circadian clock to exercise timing, offering a promising avenue for therapeutic intervention in cardiometabolic health. Here we provide an in-depth examination of the molecular mechanisms underlying skeletal muscle clock function and its impact on cardiometabolic pathways, including glucose and lipid metabolism, as well as inflammation. To highlight the role of exercise as a time-cue for the skeletal muscle clock, we discuss evidence of exercise-induced shifts in the skeletal muscle clock and the differential response to exercise performed at different times of the day. Furthermore, we present data in support of time-of-day exercise as a potential therapeutic strategy for mitigating cardiometabolic disease burden. By exploring the relationship between the skeletal muscle clock, exercise timing, and cardiometabolic health, we identify new areas for future research and offer valuable insights into novel therapeutic approaches aimed at improving cardiometabolic disease outcomes.</div></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":"198 ","pages":"Pages 36-44"},"PeriodicalIF":4.9,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142746665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}