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Cammisa I, Rigante D, Cipolla C. A Theoretical Link Between the GH/IGF-1 Axis and Cytokine Family in Children: Current Knowledge and Future Perspectives. CHILDREN (BASEL, SWITZERLAND) 2025; 12:495. [PMID: 40310145 PMCID: PMC12026182 DOI: 10.3390/children12040495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND/OBJECTIVES Growth in childhood and adolescence is influenced by a complex interaction of genetic, environmental, and hormonal factors, with growth hormone (GH) and insulin-like growth factor 1 (IGF-1) playing crucial roles in linear growth and development. However, chronic inflammation, often detected in situations like inflammatory bowel disease and juvenile idiopathic arthritis, can significantly disrupt the GH/IGF-1 axis, causing a relevant growth impairment. METHODS We conducted a retrospective review focusing on the role of cytokines in the GH-IGF-1 axis and growth. RESULTS Inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 have been shown to contribute to GH resistance through an array of mechanisms that involve the downregulation of GH receptors and alterations in IGF-1 metabolism. This disruption negatively impacts the growth plate, particularly by impairing chondrocyte proliferation and differentiation, which are essential for proper bone elongation. This review delves into the intricate relationship among growth, chronic inflammation, and GH-IGF-1 axis, emphasizing the contribution of inflammatory cytokines in modulating GH signaling. It also highlights how cytokines can interfere with the molecular pathways that regulate skeletal growth, ultimately leading to growth disturbances in children suffering from chronic inflammatory diseases. CONCLUSIONS The findings underscore the importance of controlling inflammation in affected individuals to mitigate its detrimental effects on growth and ensure that children may reach their growth full potential.
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Affiliation(s)
- Ignazio Cammisa
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
| | - Donato Rigante
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
- Department of Life Sciences and Public Health, Università Cattolica Sacro Cuore, 20123 Rome, Italy
| | - Clelia Cipolla
- Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy (C.C.)
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2
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Carter BA, Parker VE. Role of MicroRNAs in regulating sarcoplasmic reticulum calcium handling and their implications for cardiomyocyte function and heart disease. Curr Probl Cardiol 2025; 50:102980. [PMID: 39788467 DOI: 10.1016/j.cpcardiol.2025.102980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/06/2025] [Indexed: 01/12/2025]
Abstract
The regulation of calcium signaling within cardiomyocytes is pivotal for maintaining cardiac function, with disruptions in sarcoplasmic reticulum (SR) calcium handling linked to various heart diseases. This review explores the emerging role of microRNAs (miRNAs) in modulating SR calcium dynamics, highlighting their influence on cardiomyocyte maturation, function, and disease progression. We present a comprehensive overview of the mechanisms by which specific miRNAs, such as miR-1, miR-24, and miR-22, regulate key components of calcium handling, including ryanodine receptors, SERCA, and NCX. Notably, we identify critical research gaps, particularly the inconsistent findings regarding miRNA expression in heart disease and the need for standardized experimental conditions. Furthermore, we emphasize the potential of miRNAs as therapeutic targets, given their ability to influence calcium handling pathways and cardiac remodeling. The review also discusses the challenges in translating miRNA research into clinical applications, including the need for safe and effective delivery methods. By synthesizing current knowledge and identifying areas for future investigation, this review aims to provide insights into the therapeutic potential of miRNAs in diagnosing and treating heart diseases, ultimately contributing to improved patient outcomes.
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Affiliation(s)
- Benjamin Alexander Carter
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA
| | - Victoria Elizabeth Parker
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
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3
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Fei S, Rule BD, Godwin JS, Mobley CB, Roberts MD, von Walden F, Vechetti IJ. miRNA-1 regulation is necessary for mechanical overload-induced muscle hypertrophy in male mice. Physiol Rep 2025; 13:e70166. [PMID: 39761956 PMCID: PMC11705529 DOI: 10.14814/phy2.70166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in regulating gene expression post-transcriptionally. They are involved in various developmental and physiological processes, and their dysregulation is linked to various diseases. Skeletal muscle-specific miRNAs, including miR-1, play a crucial role in the development and maintenance of skeletal muscle. It has been demonstrated that the expression of miR-1 decreases by approximately 50% in response to hypertrophic stimuli, suggesting its potential involvement in muscle hypertrophy. In our study, we hypothesize that reduction of miR-1 levels is necessary for skeletal muscle growth due to its interaction to essential pro-growth genes. Promoting a smaller reduction of miR-1 levels, we observed a blunted hypertrophic response in mice undergoing a murine model of muscle hypertrophy. In addition, our results suggest that miR-1 inhibits the expression of Itm2a, a membrane-related protein, as potential miR-1-related candidate for skeletal muscle hypertrophy. While the exact mechanism in muscle hypertrophy has not been identified, our results suggest that miR-1-regulated membrane proteins are important for skeletal muscle hypertrophy.
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Affiliation(s)
- Shengyi Fei
- Department of Nutrition and Health SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | - Blake D. Rule
- Department of Nutrition and Health SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
| | | | | | | | | | - Ivan J. Vechetti
- Department of Nutrition and Health SciencesUniversity of Nebraska‐LincolnLincolnNebraskaUSA
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4
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Alivaisi E, Amini S, Haghani K, Ghaneialvar H, Keshavarzi F. Comparative effects of metformin and varying intensities of exercise on miR-133a expression in diabetic rats: Insights from machine learning analysis. Biochem Biophys Rep 2024; 40:101882. [PMID: 39649797 PMCID: PMC11625223 DOI: 10.1016/j.bbrep.2024.101882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/12/2024] [Accepted: 11/18/2024] [Indexed: 12/11/2024] Open
Abstract
This study investigated the effects of metformin, high-intensity interval training (HIIT), and moderate-intensity continuous training (MCT) on miR-133a expression in a diabetic rat model. miR-133a, a microRNA associated with skeletal muscle insulin resistance, served as a key indicator of treatment efficacy. Diabetic rats exhibited elevated miR-133a levels compared to healthy controls. Both HIIT and MCT, alone and in combination with metformin, significantly reduced miR-133a expression. Importantly, the combination of HIIT and metformin demonstrated the most potent effect, reducing miR-133a levels more than other treatments. We used the CatBoost algorithm to develop a predictive model for miR-133a expression based on metabolic parameters. The model accurately predicted miR-133a levels using body weight, blood glucose, insulin levels, and cholesterol metrics. The findings suggest a potential clinical strategy combining metformin and exercise, with miR-133a potentially serving as a biomarker for personalized diabetes management.
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Affiliation(s)
- Elahe Alivaisi
- Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
| | - Sabrieh Amini
- Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
| | - Karimeh Haghani
- Department of Clinical Biochemistry, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Hori Ghaneialvar
- Biotechnology and Medicinal Plants Research Center, Ilam University of Medical Sciences, Ilam, Iran
| | - Fatemeh Keshavarzi
- Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
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5
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Shin HE, Jang JY, Jung H, Won CW, Kim M. MicroRNAs as commonly expressed biomarkers for sarcopenia and frailty: A systematic review. Exp Gerontol 2024; 197:112600. [PMID: 39349187 DOI: 10.1016/j.exger.2024.112600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/03/2024] [Accepted: 09/27/2024] [Indexed: 10/02/2024]
Abstract
BACKGROUND Coexistent sarcopenia and frailty is more strongly associated with adverse health outcomes than each condition alone. As the importance of coexistent sarcopenia and frailty increases, exploring their underlying mechanisms is warranted. Recently, noncoding ribonucleic acids (RNAs) have been suggested as potential biomarkers of sarcopenia and frailty. This systematic review aimed to summarize noncoding RNAs commonly expressed in sarcopenia and frailty, and to search the predicted target genes and biological pathways of them. METHODS We systematically searched the literatures on PubMed, Embase, Cochrane Library, Web of Science, and Scopus for literature published till November 15, 2023. A total of 7,202 literatures were initially retrieved. After de-duplication, 34 studies (26 sarcopenia-related and 8 frailty-related) were full-text reviewed, and 15 studies (11 sarcopenia-related and 4 frailty-related) were finally included. RESULTS miR-29a-3p, miR-29b-3p, and miR-328 were identified as commonly expressed in same direction in sarcopenia and frailty. These microRNAs (miRNAs), identified in the literature search using PubMed, modulate transforming growth factor-β signaling via extracellular matrix components and calcineurin/nuclear factor of activated T cells 3 signaling via sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a, which are involved in regulating skeletal muscle fibrosis and the growth of slow-twitch muscle fibers, respectively. miR-155-5p, miR-486, and miR-23a-3p were also commonly expressed in two conditions, although in different or conflicting directions. CONCLUSION In this systematic review, we highlight the potential of shared miRNAs that exhibit consistent expression patterns as biomarkers for the early diagnosis and progression assessment of both sarcopenia and frailty.
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Affiliation(s)
- Hyung Eun Shin
- Department of Orthopaedics, Emory Musculoskeletal Institute, Emory University School of Medicine, Atlanta, GA 30329, USA; Department of Health Sciences and Technology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jae Young Jang
- Department of Biomedical Science and Technology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Heeeun Jung
- KHU-KIST Department of Converging Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Chang Won Won
- Elderly Frailty Research Center, Department of Family Medicine, College of Medicine, Kyung Hee University, Kyung Hee University Medical Center, Seoul 02447, Republic of Korea
| | - Miji Kim
- Department of Health Sciences and Technology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
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Chen G, Zou J, He Q, Xia S, Xiao Q, Du R, Zhou S, Zhang C, Wang N, Feng Y. The Role of Non-Coding RNAs in Regulating Cachexia Muscle Atrophy. Cells 2024; 13:1620. [PMID: 39404384 PMCID: PMC11482569 DOI: 10.3390/cells13191620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/17/2024] [Accepted: 09/25/2024] [Indexed: 10/19/2024] Open
Abstract
Cachexia is a late consequence of various diseases that is characterized by systemic muscle loss, with or without fat loss, leading to significant mortality. Multiple signaling pathways and molecules that increase catabolism, decrease anabolism, and interfere with muscle regeneration are activated. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in cachexia muscle atrophy. This review mainly provides the mechanisms of specific ncRNAs to regulate muscle loss during cachexia and discusses the role of ncRNAs in cachectic biomarkers and novel therapeutic strategies that could offer new insights for clinical practice.
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Affiliation(s)
- Guoming Chen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (G.C.); (C.Z.); (N.W.)
| | - Jiayi Zou
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; (J.Z.); (Q.H.)
| | - Qianhua He
- First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; (J.Z.); (Q.H.)
| | - Shuyi Xia
- Fifth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;
| | - Qili Xiao
- Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; (Q.X.); (S.Z.)
| | - Ruoxi Du
- Eighth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China;
| | - Shengmei Zhou
- Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; (Q.X.); (S.Z.)
| | - Cheng Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (G.C.); (C.Z.); (N.W.)
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (G.C.); (C.Z.); (N.W.)
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; (G.C.); (C.Z.); (N.W.)
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Abu-Toamih-Atamni HJ, Lone IM, Binenbaum I, Mott R, Pilalis E, Chatziioannou A, Iraqi FA. Mapping novel QTL and fine mapping of previously identified QTL associated with glucose tolerance using the collaborative cross mice. Mamm Genome 2024; 35:31-55. [PMID: 37978084 DOI: 10.1007/s00335-023-10025-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 10/08/2023] [Indexed: 11/19/2023]
Abstract
A chronic metabolic illness, type 2 diabetes (T2D) is a polygenic and multifactorial complicated disease. With an estimated 463 million persons aged 20 to 79 having diabetes, the number is expected to rise to 700 million by 2045, creating a significant worldwide health burden. Polygenic variants of diabetes are influenced by environmental variables. T2D is regarded as a silent illness that can advance for years before being diagnosed. Finding genetic markers for T2D and metabolic syndrome in groups with similar environmental exposure is therefore essential to understanding the mechanism of such complex characteristic illnesses. So herein, we demonstrated the exclusive use of the collaborative cross (CC) mouse reference population to identify novel quantitative trait loci (QTL) and, subsequently, suggested genes associated with host glucose tolerance in response to a high-fat diet. In this study, we used 539 mice from 60 different CC lines. The diabetogenic effect in response to high-fat dietary challenge was measured by the three-hour intraperitoneal glucose tolerance test (IPGTT) test after 12 weeks of dietary challenge. Data analysis was performed using a statistical software package IBM SPSS Statistic 23. Afterward, blood glucose concentration at the specific and between different time points during the IPGTT assay and the total area under the curve (AUC0-180) of the glucose clearance was computed and utilized as a marker for the presence and severity of diabetes. The observed AUC0-180 averages for males and females were 51,267.5 and 36,537.5 mg/dL, respectively, representing a 1.4-fold difference in favor of females with lower AUC0-180 indicating adequate glucose clearance. The AUC0-180 mean differences between the sexes within each specific CC line varied widely within the CC population. A total of 46 QTL associated with the different studied phenotypes, designated as T2DSL and its number, for Type 2 Diabetes Specific Locus and its number, were identified during our study, among which 19 QTL were not previously mapped. The genomic interval of the remaining 27 QTL previously reported, were fine mapped in our study. The genomic positions of 40 of the mapped QTL overlapped (clustered) on 11 different peaks or close genomic positions, while the remaining 6 QTL were unique. Further, our study showed a complex pattern of haplotype effects of the founders, with the wild-derived strains (mainly PWK) playing a significant role in the increase of AUC values.
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Affiliation(s)
- Hanifa J Abu-Toamih-Atamni
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel-Aviv, Israel
| | - Iqbal M Lone
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel-Aviv, Israel
| | - Ilona Binenbaum
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou Str, 11527, Athens, Greece
- Division of Pediatric Hematology-Oncology, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece
| | - Richard Mott
- Department of Genetics, University College of London, London, UK
| | | | - Aristotelis Chatziioannou
- Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, Soranou Ephessiou Str, 11527, Athens, Greece
- e-NIOS Applications PC, 196 Syggrou Ave., 17671, Kallithea, Greece
| | - Fuad A Iraqi
- Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel-Aviv, Israel.
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8
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Isailă OM, Moroianu LA, Hostiuc S. Current Trends in Biohumoral Screening for the Risk of Sudden Cardiac Death: A Systematic Review. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:418. [PMID: 38541144 PMCID: PMC10972295 DOI: 10.3390/medicina60030418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 07/23/2024]
Abstract
Background and Objectives: Sudden cardiac death (SCD) represents a challenge to health systems globally and is met with increased frequency in the population. Over time, multiple screening methods have been proposed, including the analysis of various plasma biomarkers. This article aims to analyze for illustrative purposes the specialized literature in terms of current biomarkers and testing trends, in the case of cardiovascular diseases and implicitly sudden cardiac death. Materials and Methods: In this regard, we searched the PubMed database from 2010 to the present time using the keywords "sudden cardiac death" and "biomarkers". The inclusion criteria were clinical trials that analyzed the effectiveness of screening methods in terms of biomarkers used in stratifying the risk of cardiac distress and/or sudden cardiac death. We excluded reviews, meta-analyses, and studies looking at the effectiveness of treatments. Results: An extended approach was found, through studies that brought to the forefront both classical markers analyzed by new, more performant methods, markers for other pathologies that also determined cardiovascular impact, non-specific molecules with effects on the cardiovascular system, and state-of-the-art markers, such as microRNA. Some molecules were analyzed simultaneously in certain groups of patients. Conclusion: The observed current trend revealed the tendency to define the clinical-biological particularities of the person to be screened.
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Affiliation(s)
- Oana-Maria Isailă
- Department of Legal Medicine and Bioethics, Faculty of Dentistry, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Lavinia-Alexandra Moroianu
- Clinical Medical Department, Faculty of Medicine and Pharmacy, Dunarea de Jos University, 47 Domneasca Street, 800008 Galati, Romania;
| | - Sorin Hostiuc
- Department of Legal Medicine and Bioethics, Faculty of Dentistry, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
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9
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Bou T, Ding W, Ren X, Liu H, Gong W, Jia Z, Zhang X, Dugarjaviin M, Bai D. Muscle fibre transition and transcriptional changes of horse skeletal muscles during traditional Mongolian endurance training. Equine Vet J 2024; 56:178-192. [PMID: 37345447 DOI: 10.1111/evj.13968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 04/23/2023] [Indexed: 06/23/2023]
Abstract
BACKGROUND Traditional Mongolian endurance training is an effective way to improve the athletic ability of the horse for endurance events and is widely used. This incorporates aerobic exercise and intermittent fasting and these altered physiologic conditions are associated with switches between muscle fibre types. OBJECTIVES To better understand the adaption of horse skeletal muscle to traditional Mongolian endurance training from muscle fibre characteristics and transcriptional levels and to explore possible molecular mechanisms associated with the endurance performance of horses. STUDY DESIGN Before-after study. METHODS Muscle fibre type switches and muscle transcriptome changes in six Mongolian horses were assessed during 4 weeks of training. Transcriptomic and histochemical analyses were performed. The activities of oxidative and glycolytic metabolic enzymes were analysed and we generated deep RNA-sequencing data relating to skeletal muscles. RESULTS A fast-to-slow muscle fibre transition occurred in horse skeletal muscles, with a concomitant increase of oxidative enzyme activity and decreased glycolytic enzyme activity. Numerous differentially expressed genes were involved in the control of muscle protein balance and degradation. Differential alternative splicing events were also found during training which included exon-skipping events in Ttn that were associated with muscle atrophy. Differentially expressed noncoding RNAs showed connections with muscle protein balance-related pathways and fibre type specification via the post-transcriptional regulation of miRNA. MAIN LIMITATIONS The study focuses on horse athletic ability only from the aspect of muscular adaptation. CONCLUSION Traditional Mongolian endurance training-induced muscle fibre transition and metabolic and transcriptional changes. Muscle-specific non-coding RNAs could contribute to these transcriptomic changes during training.
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Affiliation(s)
- Tugeqin Bou
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Wenqi Ding
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Xiujuan Ren
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Huiying Liu
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Wendian Gong
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Zijie Jia
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Xinzhuang Zhang
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Manglai Dugarjaviin
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
| | - Dongyi Bai
- Key Laboratory of Equus Germplasm Innovation (Co-construction by Ministry and Province), Ministry of Agriculture and Rural Affairs; Inner Mongolia Key Laboratory of Equine Genetics, Breeding and Reproduction; Equus Research Center, College of Animal Science, Inner Mongolia Agricultural University, Hohhot, China
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10
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Cimen I, Natarelli L, Abedi Kichi Z, Henderson JM, Farina FM, Briem E, Aslani M, Megens RTA, Jansen Y, Mann-Fallenbuchel E, Gencer S, Duchêne J, Nazari-Jahantigh M, van der Vorst EPC, Enard W, Döring Y, Schober A, Santovito D, Weber C. Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice. Sci Transl Med 2023; 15:eadf3357. [PMID: 37910599 DOI: 10.1126/scitranslmed.adf3357] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 10/13/2023] [Indexed: 11/03/2023]
Abstract
The CXC chemokine receptor 4 (CXCR4) in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is crucial for vascular integrity. The atheroprotective functions of CXCR4 in vascular cells may be counteracted by atherogenic functions in other nonvascular cell types. Thus, strategies for cell-specifically augmenting CXCR4 function in vascular cells are crucial if this receptor is to be useful as a therapeutic target in treating atherosclerosis and other vascular disorders. Here, we identified miR-206-3p as a vascular-specific CXCR4 repressor and exploited a target-site blocker (CXCR4-TSB) that disrupted the interaction of miR-206-3p with CXCR4 in vitro and in vivo. In vitro, CXCR4-TSB enhanced CXCR4 expression in human and murine ECs and VSMCs to modulate cell viability, proliferation, and migration. Systemic administration of CXCR4-TSB in Apoe-deficient mice enhanced Cxcr4 expression in ECs and VSMCs in the walls of blood vessels, reduced vascular permeability and monocyte adhesion to endothelium, and attenuated the development of diet-induced atherosclerosis. CXCR4-TSB also increased CXCR4 expression in B cells, corroborating its atheroprotective role in this cell type. Analyses of human atherosclerotic plaque specimens revealed a decrease in CXCR4 and an increase in miR-206-3p expression in advanced compared with early lesions, supporting a role for the miR-206-3p-CXCR4 interaction in human disease. Disrupting the miR-206-3p-CXCR4 interaction in a cell-specific manner with target-site blockers is a potential therapeutic approach that could be used to treat atherosclerosis and other vascular diseases.
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Affiliation(s)
- Ismail Cimen
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Lucia Natarelli
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Zahra Abedi Kichi
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - James M Henderson
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
| | - Floriana M Farina
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
| | - Eva Briem
- Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians-Universität München, 85152 Planegg-Martinsried, Germany
| | - Maria Aslani
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Remco T A Megens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
- Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6200 MD Maastricht, Netherlands
| | - Yvonne Jansen
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Elizabeth Mann-Fallenbuchel
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Selin Gencer
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
| | - Johan Duchêne
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
| | - Maliheh Nazari-Jahantigh
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
| | - Emiel P C van der Vorst
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, 52074 Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, 52062 Aachen, Germany
| | - Wolfgang Enard
- Anthropology and Human Genomics, Faculty of Biology, Ludwig-Maximilians-Universität München, 85152 Planegg-Martinsried, Germany
| | - Yvonne Döring
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
- Department of Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, 3010 Bern, Switzerland
| | - Andreas Schober
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
| | - Donato Santovito
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
- Institute of Genetic and Biomedical Research (IRGB), Unit of Milan, National Research Council (CNR), 20090 Milan, Italy
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, 80336 Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80336 Munich, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 HX Maastricht, Netherlands
- Munich Cluster for Systems Neurology (SyNergy), 81337 Munich, Germany
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11
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Sharma AK, Bisht P, Gupta B, Sayeed Akhtar MD, Shaik Alavudeen S, Afzal O, Sa Altamimi A. Investigating miRNA subfamilies: Can they assist in the early diagnosis of acute myocardial infarction? Drug Discov Today 2023; 28:103695. [PMID: 37406730 DOI: 10.1016/j.drudis.2023.103695] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/04/2023] [Accepted: 06/28/2023] [Indexed: 07/07/2023]
Abstract
This report focuses on small non-coding RNA molecules (miRNAs), which have emerged as potential biomarkers with variable diagnostic values and false-positives in different conditions that limit their clinical preference. Current investigations focus on small non-coding RNA molecules (miRNAs), which have emerged as potential biomarkers with variable diagnostic values and false-positives in different conditions that limit their clinical preference. We thoroughly scrutinize the leading pathology of myocardial infarction and contemporary alterations in miRNAs for their specificity, stability and significant prognostic value at the early stage of acute myocardial infarction (AMI). Based on secondary data analysis, we explore common biomarkers and further investigate included miRNA biomarkers for their specificity, stability and area under the curve (AUC) values. We conclude that a group of novel biomarkers, including miRNA-1, miRNA-208a/b and miRNA-499, could help predict the emergence of AMI at an early stage.
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Affiliation(s)
- Arun K Sharma
- Department of Cardiovascular Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana 122413, India.
| | - Priyanka Bisht
- Department of Cardiovascular Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana 122413, India
| | - Bishal Gupta
- Department of Cardiovascular Pharmacology, Amity Institute of Pharmacy, Amity University, Gurugram, Haryana 122413, India
| | - M D Sayeed Akhtar
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, AlFara, Abha 62223, Saudi Arabia.
| | - Sirajudeen Shaik Alavudeen
- Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, AlFara, Abha 62223, Saudi Arabia
| | - Obaid Afzal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Abdulmalik Sa Altamimi
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
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12
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Shariati A, Shahabi Raberi V, Masumi M, Tarbiat A, Rastgoo E, Faramarz Zadeh R. The Regulation of Pyroptosis and Ferroptosis by MicroRNAs in Cardiovascular Diseases. Galen Med J 2023; 12:e2933. [PMID: 38974133 PMCID: PMC11227648 DOI: 10.31661/gmj.v12i0.2933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 04/01/2023] [Accepted: 04/09/2023] [Indexed: 07/09/2024] Open
Abstract
Cardiovascular diseases (CVDs) are considered the most prevalent noncommunicable disease and the leading cause of death worldwide. A plethora of evidence has revealed that microRNAs (miRNAs) could control the inhibition or progression of CVDs by regulating pivotal cell processes ranging from metabolism and homeostasis to programmed cell death (PCD). Pyroptosis and ferroptosis are two major types of nonapoptotic PCDs involved in the pathogenesis of heart failure. However, no study has discussed the crosstalk between miRNAs and these two types of PCDs in the CVDs. The current review demonstrated that different types of miRNAs can regulate both ferroptosis and pyroptosis and thereby affect CVDs progression and inhibition. Altogether, the discussed content encourages further studies to confirm that mentioned pathways are suitable to be considered as novel therapeutic approaches against CVDs.
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Affiliation(s)
- Akram Shariati
- Department of Cardiology, School of Medicine, Urmia University of Medical Sciences,
Urmia, Iran
| | - Venus Shahabi Raberi
- Seyed-Al-Shohada Cardiology Hospital, Urmia University of Medical Sciences, Urmia,
Iran
| | - Mehdi Masumi
- Seyed-Al-Shohada Cardiology Hospital, Urmia University of Medical Sciences, Urmia,
Iran
| | - Ali Tarbiat
- Seyed-Al-Shohada Cardiology Hospital, Urmia University of Medical Sciences, Urmia,
Iran
| | - Elham Rastgoo
- Department of Radiology, School of Medicine, Shiraz University of Medical Sciences,
Shiraz, Iran
| | - Reza Faramarz Zadeh
- Seyed-Al-Shohada Cardiology Hospital, Urmia University of Medical Sciences, Urmia,
Iran
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13
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Li K, Ma L, Lu Z, Yan L, Chen W, Wang B, Xu H, Asemi Z. Apoptosis and heart failure: The role of non-coding RNAs and exosomal non-coding RNAs. Pathol Res Pract 2023; 248:154669. [PMID: 37422971 DOI: 10.1016/j.prp.2023.154669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 07/01/2023] [Accepted: 07/02/2023] [Indexed: 07/11/2023]
Abstract
Heart failure is a condition that affects the cardio vascular system and occurs if the heart cannot adequately pump the oxygen and blood to the body. Myocardial infarction, reperfusion injury, and this disease is the only a few examples of the numerous cardiovascular illnesses that are impacted by the closely controlled cell deletion process known as apoptosis. Attention has been paid to the creation of alternative diagnostic and treatment modalities for the condition. Recent evidences have shown that some non-coding RNAs (ncRNAs) influence the stability of proteins, control of transcription factors, and HF apoptosis through a variety of methods. Exosomes make a significant paracrine contribution to the regulation of illnesses as well as to the communication between nearby and distant organs. However, it has not yet been determined whether exosomes regulate the cardiomyocyte-tumor cell interaction in ischemia HF to limit the vulnerability of malignancy to ferroptosis. Here, we list the numerous ncRNAs in HF that are connected to apoptosis. In addition, we emphasize the significance of exosomal ncRNAs in the HF.
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Affiliation(s)
- Ketao Li
- Department of cardiology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310022, China
| | - Liping Ma
- Department of cardiology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310022, China
| | - Zhiwei Lu
- Hangzhou Heyunjia Hospital, Hangzhou, Zhe'jiang 310000, China
| | - Laixing Yan
- Department of cardiology, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang 310022, China
| | - Wan Chen
- Department of Cardiology, Jiulongpo First People's Hospital, Chongqing 400051, China
| | - Bing Wang
- Department of cardiology, Zouping People's Hospital, Zouping, Shandong 256299, China
| | - Huiju Xu
- Department of cardiology, Hangzhou Mingzhou Hospital, Hangzhou, Zhe'jiang 311215, China.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
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14
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Macvanin MT, Gluvic Z, Bajic V, Isenovic ER. Novel insights regarding the role of noncoding RNAs in diabetes. World J Diabetes 2023; 14:958-976. [PMID: 37547582 PMCID: PMC10401459 DOI: 10.4239/wjd.v14.i7.958] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/01/2023] [Accepted: 05/22/2023] [Indexed: 07/12/2023] Open
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders defined by hyperglycemia induced by insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. In 2021, the global prevalence of diabetes is anticipated to be 10.7% (537 million people). Noncoding RNAs (ncRNAs) appear to have an important role in the initiation and progression of DM, according to a growing body of research. The two major groups of ncRNAs implicated in diabetic disorders are miRNAs and long noncoding RNAs. miRNAs are single-stranded, short (17-25 nucleotides), ncRNAs that influence gene expression at the post-transcriptional level. Because DM has reached epidemic proportions worldwide, it appears that novel diagnostic and therapeutic strategies are required to identify and treat complications associated with these diseases efficiently. miRNAs are gaining attention as biomarkers for DM diagnosis and potential treatment due to their function in maintaining physiological homeostasis via gene expression regulation. In this review, we address the issue of the gradually expanding global prevalence of DM by presenting a complete and up-to-date synopsis of various regulatory miRNAs involved in these disorders. We hope this review will spark discussion about ncRNAs as prognostic biomarkers and therapeutic tools for DM. We examine and synthesize recent research that used novel, high-throughput technologies to uncover ncRNAs involved in DM, necessitating a systematic approach to examining and summarizing their roles and possible diagnostic and therapeutic uses.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Zoran Gluvic
- Department of Endocrinology and Diabetes, Clinic for Internal Medicine, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade 11000, Serbia
| | - Vladan Bajic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade 11000, Serbia
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15
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Grieb A, Schmitt A, Fragasso A, Widmann M, Mattioni Maturana F, Burgstahler C, Erz G, Schellhorn P, Nieß AM, Munz B. Skeletal Muscle MicroRNA Patterns in Response to a Single Bout of Exercise in Females: Biomarkers for Subsequent Training Adaptation? Biomolecules 2023; 13:884. [PMID: 37371465 DOI: 10.3390/biom13060884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/18/2023] [Accepted: 05/20/2023] [Indexed: 06/29/2023] Open
Abstract
microRNAs (miRs) have been proposed as a promising new class of biomarkers in the context of training adaptation. Using microarray analysis, we studied skeletal muscle miR patterns in sedentary young healthy females (n = 6) before and after a single submaximal bout of endurance exercise ('reference training'). Subsequently, participants were subjected to a structured training program, consisting of six weeks of moderate-intensity continuous endurance training (MICT) and six weeks of high-intensity interval training (HIIT) in randomized order. In vastus lateralis muscle, we found significant downregulation of myomiRs, specifically miR-1, 133a-3p, and -5p, -133b, and -499a-5p. Similarly, exercise-associated miRs-23a-3p, -378a-5p, -128-3p, -21-5p, -107, -27a-3p, -126-3p, and -152-3p were significantly downregulated, whereas miR-23a-5p was upregulated. Furthermore, in an untargeted approach for differential expression in response to acute exercise, we identified n = 35 miRs that were downregulated and n = 20 miRs that were upregulated by factor 4.5 or more. Remarkably, KEGG pathway analysis indicated central involvement of this set of miRs in fatty acid metabolism. To reproduce these data in a larger cohort of all-female subjects (n = 29), qPCR analysis was carried out on n = 15 miRs selected from the microarray, which confirmed their differential expression. Furthermore, the acute response, i.e., the difference between miR concentrations before and after the reference training, was correlated with changes in maximum oxygen uptake (V̇O2max) in response to the training program. Here, we found that miRs-199a-3p and -19b-3p might be suitable acute-response candidates that correlate with individual degrees of training adaptation in females.
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Affiliation(s)
- Alexandra Grieb
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Angelika Schmitt
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Annunziata Fragasso
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Manuel Widmann
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Felipe Mattioni Maturana
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Christof Burgstahler
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Gunnar Erz
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Philipp Schellhorn
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Andreas M Nieß
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
| | - Barbara Munz
- Medical Clinic, Department of Sports Medicine, University Hospital Tübingen, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
- Interfaculty Research Institute for Sports and Physical Activity, Eberhard Karls University of Tübingen, D-72074 Tübingen, Germany
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16
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Dimasi CG, Darby JRT, Morrison JL. A change of heart: understanding the mechanisms regulating cardiac proliferation and metabolism before and after birth. J Physiol 2023; 601:1319-1341. [PMID: 36872609 PMCID: PMC10952280 DOI: 10.1113/jp284137] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Accepted: 02/17/2023] [Indexed: 03/07/2023] Open
Abstract
Mammalian cardiomyocytes undergo major maturational changes in preparation for birth and postnatal life. Immature cardiomyocytes contribute to cardiac growth via proliferation and thus the heart has the capacity to regenerate. To prepare for postnatal life, structural and metabolic changes associated with increased cardiac output and function must occur. This includes exit from the cell cycle, hypertrophic growth, mitochondrial maturation and sarcomeric protein isoform switching. However, these changes come at a price: the loss of cardiac regenerative capacity such that damage to the heart in postnatal life is permanent. This is a significant barrier to the development of new treatments for cardiac repair and contributes to heart failure. The transitional period of cardiomyocyte growth is a complex and multifaceted event. In this review, we focus on studies that have investigated this critical transition period as well as novel factors that may regulate and drive this process. We also discuss the potential use of new biomarkers for the detection of myocardial infarction and, in the broader sense, cardiovascular disease.
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Affiliation(s)
- Catherine G. Dimasi
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health SciencesUniversity of South AustraliaAdelaideSAAustralia
| | - Jack R. T. Darby
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health SciencesUniversity of South AustraliaAdelaideSAAustralia
| | - Janna L. Morrison
- Early Origins of Adult Health Research Group, Health and Biomedical Innovation, UniSA: Clinical and Health SciencesUniversity of South AustraliaAdelaideSAAustralia
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17
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Macvanin M, Gluvic Z, Radovanovic J, Essack M, Gao X, Isenovic ER. New insights on the cardiovascular effects of IGF-1. Front Endocrinol (Lausanne) 2023; 14:1142644. [PMID: 36843588 PMCID: PMC9947133 DOI: 10.3389/fendo.2023.1142644] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023] Open
Abstract
INTRODUCTION Cardiovascular (CV) disorders are steadily increasing, making them the world's most prevalent health issue. New research highlights the importance of insulin-like growth factor 1 (IGF-1) for maintaining CV health. METHODS We searched PubMed and MEDLINE for English and non-English articles with English abstracts published between 1957 (when the first report on IGF-1 identification was published) and 2022. The top search terms were: IGF-1, cardiovascular disease, IGF-1 receptors, IGF-1 and microRNAs, therapeutic interventions with IGF-1, IGF-1 and diabetes, IGF-1 and cardiovascular disease. The search retrieved original peer-reviewed articles, which were further analyzed, focusing on the role of IGF-1 in pathophysiological conditions. We specifically focused on including the most recent findings published in the past five years. RESULTS IGF-1, an anabolic growth factor, regulates cell division, proliferation, and survival. In addition to its well-known growth-promoting and metabolic effects, there is mounting evidence that IGF-1 plays a specialized role in the complex activities that underpin CV function. IGF-1 promotes cardiac development and improves cardiac output, stroke volume, contractility, and ejection fraction. Furthermore, IGF-1 mediates many growth hormones (GH) actions. IGF-1 stimulates contractility and tissue remodeling in humans to improve heart function after myocardial infarction. IGF-1 also improves the lipid profile, lowers insulin levels, increases insulin sensitivity, and promotes glucose metabolism. These findings point to the intriguing medicinal potential of IGF-1. Human studies associate low serum levels of free or total IGF-1 with an increased risk of CV and cerebrovascular illness. Extensive human trials are being conducted to investigate the therapeutic efficacy and outcomes of IGF-1-related therapy. DISCUSSION We anticipate the development of novel IGF-1-related therapy with minimal side effects. This review discusses recent findings on the role of IGF-1 in the cardiovascular (CVD) system, including both normal and pathological conditions. We also discuss progress in therapeutic interventions aimed at targeting the IGF axis and provide insights into the epigenetic regulation of IGF-1 mediated by microRNAs.
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Affiliation(s)
- Mirjana Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran Gluvic
- Clinic for Internal Medicine, Department of Endocrinology and Diabetes, Zemun Clinical Hospital, School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jelena Radovanovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Magbubah Essack
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Xin Gao
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
- Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division (CEMSE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Esma R. Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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18
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Hu Q, Xu L, Yi Q, Yuan J, Wu G, Wang Y. miR-204 suppresses uveal melanoma cell migration and invasion through negative regulation of RAB22A. Funct Integr Genomics 2023; 23:49. [PMID: 36705739 DOI: 10.1007/s10142-022-00953-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/28/2023]
Abstract
Uveal melanoma (UM), a frequently seen adulthood primary ocular malignancy, shows high aggressiveness. Accumulating studies have revealed the crucial effects of microRNAs (miRNAs) on tumorigenesis and development in various human tumors. miR-204, the cancer-associated miRNA, shows dysregulation and is related to several human malignancies, but its effect on UM remains unknown. The present work focused on exploring miR-204's effect on UM and elucidating its possible molecular mechanisms. According to our results, miR-204 expression markedly increased within both UM tissues and cell lines. As revealed by functional analysis, miR-204 suppressed UM cell invasion and migration. Besides, RAB22A expression decreased through directly binding miR-204 into the corresponding 3' untranslated region (3'UTR) in UM cells. Furthermore, the RAB22A mRNA level increased, which was negatively related to the miR-204 level within UM samples. As revealed by mechanical research, miR-204 exerted its inhibition on the invasion and migration of UM cells via RAB22A. Taken together, this study suggested the tumor-suppressing effect of miR-204 on UM through down-regulating RAB22A. Thus, miR-204 may serve as the new anti-UM therapeutic target.
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Affiliation(s)
- Qidi Hu
- Department of Ophthalmology, The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, No. 599 Beimingcheng Road, Ningbo, 315040, China
| | - Lingli Xu
- Department of Ophthalmology, The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, No. 599 Beimingcheng Road, Ningbo, 315040, China
| | - Quanyong Yi
- Department of Ophthalmology, The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, No. 599 Beimingcheng Road, Ningbo, 315040, China
| | - Jianshu Yuan
- Department of Ophthalmology, The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, No. 599 Beimingcheng Road, Ningbo, 315040, China
| | - Guohai Wu
- Department of Ophthalmology, The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, No. 599 Beimingcheng Road, Ningbo, 315040, China
| | - Yuwen Wang
- Department of Ophthalmology, The Affiliated Ningbo Eye Hospital of Wenzhou Medical University, No. 599 Beimingcheng Road, Ningbo, 315040, China.
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19
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Ageing at Molecular Level: Role of MicroRNAs. Subcell Biochem 2023; 102:195-248. [PMID: 36600135 DOI: 10.1007/978-3-031-21410-3_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The progression of age triggers a vast number of diseases including cardiovascular, cancer, and neurodegenerative disorders. Regardless of our plentiful knowledge about age-related diseases, little is understood about molecular pathways that associate the ageing process with various diseases. Several cellular events like senescence, telomere dysfunction, alterations in protein processing, and regulation of gene expression are common between ageing and associated diseases. Accumulating information on the role of microRNAs (miRNAs) suggests targeting miRNAs can aid our understanding of the interplay between ageing and associated diseases. In the present chapter, we have attempted to explore the information available on the role of miRNAs in ageing of various tissues/organs and diseases and understand the molecular mechanism of ageing.
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20
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Liu C, Cao Y, Li L, Wang Y, Meng Q. Overexpression of miR-29ab1 Cluster Results in Excessive Muscle Growth in 1-Month-old Mice by Inhibiting Mstn. DNA Cell Biol 2023; 42:43-52. [PMID: 36576412 DOI: 10.1089/dna.2022.0247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Skeletal muscle mass is closely related to strength and health. Multiple genes and signaling pathways are involved in the regulation of skeletal muscle hypertrophy. miR-29 can participate in various processes of skeletal muscle development through different target genes. However, studies are needed on the function of miR-29 in skeletal muscle during mouse puberty. We used mice in which overexpression of miR-29ab1 cluster could be induced specifically within skeletal muscle, and investigated the effects of miR-29 overexpression on skeletal muscle at 1 month of age. We found that the overexpression of miR-29ab1 cluster in juvenile mice caused skeletal muscle mass and myofiber cross-sectional area to increase. The study on the mechanism of miR-29 inducing skeletal muscle hypertrophy had found that miR-29 achieved its function by inhibiting the expression of Mstn. At the same time, injured myofibers were present within miR-29ab1 cluster overexpressing skeletal muscle. The damage of skeletal muscle may be due to the inhibition of the type IV collagen by miR-29. These results indicate that although the overexpression of miR-29ab1 cluster can induce skeletal muscle hypertrophy in mouse juvenile, it simultaneously causes skeletal muscle damage.
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Affiliation(s)
- Chuncheng Liu
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.,Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, China
| | - Yuxin Cao
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Science, China Agricultural University, Beijing, China
| | - Lei Li
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Science, China Agricultural University, Beijing, China
| | - Yiting Wang
- Inner Mongolia Key Laboratory of Functional Genome Bioinformatics, School of Life Science and Technology, Inner Mongolia University of Science and Technology, Baotou, China
| | - Qingyong Meng
- The State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China.,Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Science, China Agricultural University, Beijing, China
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21
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Going nuclear: Molecular adaptations to exercise mediated by myonuclei. SPORTS MEDICINE AND HEALTH SCIENCE 2022; 5:2-9. [PMID: 36994170 PMCID: PMC10040379 DOI: 10.1016/j.smhs.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/23/2022] [Accepted: 11/30/2022] [Indexed: 12/13/2022] Open
Abstract
Muscle fibers are multinucleated, and muscle fiber nuclei (myonuclei) are believed to be post-mitotic and are typically situated near the periphery of the myofiber. Due to the unique organization of muscle fibers and their nuclei, the cellular and molecular mechanisms regulating myofiber homeostasis in unstressed and stressed conditions (e.g., exercise) are unique. A key role myonuclei play in regulating muscle during exercise is gene transcription. Only recently have investigators had the capability to identify molecular changes at high resolution exclusively in myonuclei in response to perturbations in vivo. The purpose of this review is to describe how myonuclei modulate their transcriptome, epigenetic status, mobility and shape, and microRNA expression in response to exercise in vivo. Given the relative paucity of high-fidelity information on myonucleus-specific contributions to exercise adaptation, we identify specific gaps in knowledge and provide perspectives on future directions of research.
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22
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Molecular mechanisms of exercise contributing to tissue regeneration. Signal Transduct Target Ther 2022; 7:383. [PMID: 36446784 PMCID: PMC9709153 DOI: 10.1038/s41392-022-01233-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 10/03/2022] [Accepted: 10/17/2022] [Indexed: 12/03/2022] Open
Abstract
Physical activity has been known as an essential element to promote human health for centuries. Thus, exercise intervention is encouraged to battle against sedentary lifestyle. Recent rapid advances in molecular biotechnology have demonstrated that both endurance and resistance exercise training, two traditional types of exercise, trigger a series of physiological responses, unraveling the mechanisms of exercise regulating on the human body. Therefore, exercise has been expected as a candidate approach of alleviating a wide range of diseases, such as metabolic diseases, neurodegenerative disorders, tumors, and cardiovascular diseases. In particular, the capacity of exercise to promote tissue regeneration has attracted the attention of many researchers in recent decades. Since most adult human organs have a weak regenerative capacity, it is currently a key challenge in regenerative medicine to improve the efficiency of tissue regeneration. As research progresses, exercise-induced tissue regeneration seems to provide a novel approach for fighting against injury or senescence, establishing strong theoretical basis for more and more "exercise mimetics." These drugs are acting as the pharmaceutical alternatives of those individuals who cannot experience the benefits of exercise. Here, we comprehensively provide a description of the benefits of exercise on tissue regeneration in diverse organs, mainly focusing on musculoskeletal system, cardiovascular system, and nervous system. We also discuss the underlying molecular mechanisms associated with the regenerative effects of exercise and emerging therapeutic exercise mimetics for regeneration, as well as the associated opportunities and challenges. We aim to describe an integrated perspective on the current advances of distinct physiological mechanisms associated with exercise-induced tissue regeneration on various organs and facilitate the development of drugs that mimics the benefits of exercise.
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23
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Cheng M, Yang Z, Qiao L, Yang Y, Deng Y, Zhang C, Mi T. AGEs induce endothelial cells senescence and endothelial barrier dysfunction via miR-1-3p/MLCK signaling pathways. Gene 2022; 851:147030. [DOI: 10.1016/j.gene.2022.147030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 10/10/2022] [Accepted: 10/31/2022] [Indexed: 11/08/2022]
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24
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Zhao H, Li P, Wang J. The role of muscle-specific MicroRNAs in patients with chronic obstructive pulmonary disease and skeletal muscle dysfunction. Front Physiol 2022; 13:954364. [PMID: 36338492 PMCID: PMC9633658 DOI: 10.3389/fphys.2022.954364] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 10/11/2022] [Indexed: 11/27/2022] Open
Abstract
Skeletal muscle dysfunction is a systematic manifestation of chronic obstructive pulmonary disease (COPD), which is manifested through the changes in the respiratory and peripheral muscle fiber types, reducing muscle strength and endurance, and muscle atrophy. Muscle dysfunction limits the daily mobility, negatively affects the quality of life, and may increase the patient’s risk of mortality. MicroRNAs (miRNAs) as the regulators of gene expression, plays an important role in modulating skeletal muscle dysfunction in COPD by regulating skeletal muscle development (proliferation, differentiation), protein synthesis and degradation, inflammatory response, and metabolism. In particular, muscle-specific miRNAs (myomiRs) may play an important role in this process, although the different expression levels of myomiRs in COPD and skeletal muscle dysfunction and the mechanisms underlying their role remain unclear. In this paper, we review the differential expression of the myomiRs in COPD to identify myomiRs that play a role in skeletal muscle dysfunction in COPD. We further explore their possible mechanisms and action in order to provide new ideas for the prevention and treatment of the skeletal muscle dysfunction in COPD.
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Affiliation(s)
- Hui Zhao
- Department of Sports Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Peijun Li
- Department of Sports Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Jihong Wang
- School of Physical Education, Shanghai University of Sport, Shanghai, China
- *Correspondence: Jihong Wang,
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25
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Xu R, Fu J, Hu Y, Yang X, Tao X, Chen L, Huang K, Fu Q. Roflumilast-Mediated Phosphodiesterase 4D Inhibition Reverses Diabetes-Associated Cardiac Dysfunction and Remodeling: Effects Beyond Glucose Lowering. Diabetes 2022; 71:1660-1678. [PMID: 35594380 DOI: 10.2337/db21-0898] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 05/02/2022] [Indexed: 11/13/2022]
Abstract
Patients with type 2 diabetes have a substantial risk of developing cardiovascular disease. Phosphodiesterase 4 (PDE4) dysregulation is of pathophysiological importance in metabolic disorders. For determination of the role of PDE4 in diabetic cardiac dysfunction, mice fed with a high-fat diet (HFD) were treated by pharmacological inhibition of PDE4 or cardiac specific knocking down of PDE4D. Mice on HFD developed diabetes and cardiac dysfunction with increased cardiac PDE4D5 expression. PDE4 inhibitor roflumilast can reverse hyperglycemia and cardiac dysfunction, accompanied by the decrease of PDE4D expression and increase of muscle specific miRNA miR-1 level in hearts. Either cardiac specific PDE4D knockdown or miR-1 overexpression significantly reversed cardiac dysfunction in HFD mice, despite persistence of hyperglycemia. Findings of gain- and loss-of-function studies of PDE4D in cardiomyocytes indicated that inhibition of insulin-induced PDE4D protected cardiac hypertrophy by preserving miR-1 expression in cardiomyocytes through promoting cAMP-CREB-Sirt1 signaling-induced SERCA2a expression. We further revealed that insulin also induced PDE4D expression in cardiac fibroblasts, which causes cardiac fibrosis through TGF-β1 signaling-mediated miR-1 reduction. Importantly, the expression of PDE4D5 was increased in human failing hearts of individuals with diabetes. These studies elucidate a novel mechanism by which hyperinsulinemia-induced cardiac PDE4D expression contributes to diabetic cardiac remodeling through reducing the expression of miR-1 and upregulation of miR-1 target hypertrophy and fibrosis-associated genes. Our study suggests a therapeutic potential of PDE4 inhibitor roflumilast in preventing or treating cardiac dysfunction in diabetes in addition to lowering glucose.
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Affiliation(s)
- Rui Xu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Jing Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Yuting Hu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoyan Yang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Xiang Tao
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Long Chen
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Huang
- Clinical Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
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26
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Yu FSX, Lee PSY, Yang L, Gao N, Zhang Y, Ljubimov AV, Yang E, Zhou Q, Xie L. The impact of sensory neuropathy and inflammation on epithelial wound healing in diabetic corneas. Prog Retin Eye Res 2022; 89:101039. [PMID: 34991965 PMCID: PMC9250553 DOI: 10.1016/j.preteyeres.2021.101039] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 12/10/2021] [Accepted: 12/20/2021] [Indexed: 02/08/2023]
Abstract
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, with several underlying pathophysiological mechanisms, some of which are still uncertain. The cornea is an avascular tissue and sensitive to hyperglycemia, resulting in several diabetic corneal complications including delayed epithelial wound healing, recurrent erosions, neuropathy, loss of sensitivity, and tear film changes. The manifestation of DPN in the cornea is referred to as diabetic neurotrophic keratopathy (DNK). Recent studies have revealed that disturbed epithelial-neural-immune cell interactions are a major cause of DNK. The epithelium is supplied by a dense network of sensory nerve endings and dendritic cell processes, and it secretes growth/neurotrophic factors and cytokines to nourish these neighboring cells. In turn, sensory nerve endings release neuropeptides to suppress inflammation and promote epithelial wound healing, while resident immune cells provide neurotrophic and growth factors to support neuronal and epithelial cells, respectively. Diabetes greatly perturbs these interdependencies, resulting in suppressed epithelial proliferation, sensory neuropathy, and a decreased density of dendritic cells. Clinically, this results in a markedly delayed wound healing and impaired sensory nerve regeneration in response to insult and injury. Current treatments for DPN and DNK largely focus on managing the severe complications of the disease. Cell-based therapies hold promise for providing more effective treatment for diabetic keratopathy and corneal ulcers.
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Affiliation(s)
- Fu-Shin X Yu
- Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
| | - Patrick S Y Lee
- Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Lingling Yang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Nan Gao
- Departments of Ophthalmology and Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Yangyang Zhang
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Alexander V Ljubimov
- Departments of Biomedical Sciences and Neurosurgery, Cedars-Sinai Medical Center, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ellen Yang
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA
| | - Qingjun Zhou
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China
| | - Lixin Xie
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.
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27
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Conway J, Certo M, Lord JM, Mauro C, Duggal NA. Understanding the role of host metabolites in the induction of immune senescence: Future strategies for keeping the ageing population healthy. Br J Pharmacol 2022; 179:1808-1824. [PMID: 34435354 DOI: 10.1111/bph.15671] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/12/2021] [Accepted: 08/19/2021] [Indexed: 12/24/2022] Open
Abstract
Advancing age is accompanied by significant remodelling of the immune system, termed immune senescence, and increased systemic inflammation, termed inflammageing, both of which contribute towards an increased risk of developing chronic diseases in old age. Age-associated alterations in metabolic homeostasis have been linked with changes in a range of physiological functions, but their effects on immune senescence remains poorly understood. In this article, we review the recent literature to formulate hypotheses as to how an age-associated dysfunctional metabolism, driven by an accumulation of key host metabolites (saturated fatty acids, cholesterol, ceramides and lactate) and loss of other metabolites (glutamine, tryptophan and short-chain fatty acids), might play a role in driving immune senescence and inflammageing, ultimately leading to diseases of old age. We also highlight the potential use of metabolic immunotherapeutic strategies targeting these processes in counteracting immune senescence and restoring immune homeostasis in older adults. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.
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Affiliation(s)
- Jessica Conway
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK
| | - Michelangelo Certo
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
| | - Janet M Lord
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK
- NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham and University of Birmingham, Birmingham, UK
| | - Claudio Mauro
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK
| | - Niharika A Duggal
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Birmingham, Birmingham, UK
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28
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Wang J, Huang Y, Xu J, Yue B, Wen Y, Wang X, Lei C, Chen H. Pleomorphic adenoma gene 1 (PLAG1) promotes proliferation and inhibits apoptosis of bovine primary myoblasts through the PI3K-Akt signaling pathway. J Anim Sci 2022; 100:6553189. [PMID: 35325183 PMCID: PMC9030145 DOI: 10.1093/jas/skac098] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/22/2022] [Indexed: 11/12/2022] Open
Abstract
Pleomorphic adenoma gene 1 (PLAG1) is a transcription factor involved in various cellular processes in organismal growth and development. However, its role in muscle function is unclear. This work investigated the roles of PLAG1 in muscle development and explored its regulatory mechanisms. The PLAG1 was proved to promote the proliferation of bovine primary myoblasts using the cell counting kit 8 (CCK-8) assay (P < 0.001), 5-ethynyl-2'-deoxyuridine (EdU) proliferation assay (P = 0.005), quantitative real-time polymerase chain reaction (qRT-PCR) (P = 0.028), western blot, and flow cytometry (P < 0.05), and to inhibit apoptosis of bovine primary myoblasts using qRT-PCR (P = 0.038), western blot, and flow cytometry (P < 0.001). Chromatin immunoprecipitation sequencing (ChIP-seq) and western blot showed PLAG1 upregulated phosphorylated (p)-PI3K, PI3K, p-Akt, Akt, Cyclin D1, and CDK2 and inhibited the expression of p21 and p27 to enhance myoblast proliferation, and increased expression of Bcl-2, and Bcl-xL to inhibit apoptosis. Additionally, PLAG1 was identified as a target of miR-1 using dual-luciferase assay (P < 0.001), qRT-PCR (P < 0.001), and western blot. Furthermore, miR-1 might be a potential mediator of the positive feedback regulation relationship between PLAG1 and the PI3K-Akt signaling pathway.
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Affiliation(s)
- Jian Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Yongzhen Huang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Jiawei Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Binglin Yue
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Yifan Wen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiao Wang
- Bagsværdvej 103, ST., Konge Larsen ApS, 2800 Kongens Lyngby, Denmark
| | - Chuzhao Lei
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Hong Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
- Corresponding author:
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29
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The effects of aerobic exercise on blood plasma microRNA level in healthy adults: a systematic review and meta-analysis. SPORT SCIENCES FOR HEALTH 2022. [DOI: 10.1007/s11332-022-00914-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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30
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MicroRNA-100 Reduced Fetal Bovine Muscle Satellite Cell Myogenesis and Augmented Intramuscular Lipid Deposition by Modulating IGF1R. Cells 2022; 11:cells11030451. [PMID: 35159261 PMCID: PMC8833961 DOI: 10.3390/cells11030451] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/10/2022] [Accepted: 01/26/2022] [Indexed: 02/01/2023] Open
Abstract
Previously, microRNA-100 (miR-100) and its putative mRNA target, insulin-like growth factor receptor-1 (IGF1R) were identified as differentially and inversely expressed in bovine longissimus dorsi (LD) muscles with divergent intramuscular fat (IMF) content by our group. While IGF1R signaling is implicated in myogenesis and muscle lipid metabolism, the underlying regulatory mechanisms are poorly understood. In the present study, we aimed to investigate the regulation of IGF1R by miR-100 during bovine muscle satellite cell (BMSC) myogenesis and lipid deposition. MiR-100 was confirmed to target the IGF1R 3′-untranslated region (3′-UTR) by luciferase reporter assay. Furthermore, expression of miR-100 and IGF1R was reciprocal during BMSC differentiation, suggesting a crosstalk between the two. Correspondingly, miR-100 mimic (agomiR) suppressed the levels of IGF1R, PI3K/AKT pathway signaling, myogenic gene MYOG, muscle structural components MYH7 and MYH8, whereas the inhibitor (antagomiR) had no clear stimulating effects. The IGF1R inhibitor (BMS-754807) curtailed receptor levels and triggered atrophy in muscle myotubes but did not influence miR-100 expression. AgomiR increased oleic acid-induced lipid deposition in BMSC myotubes supporting its involvement in intramuscular fat deposition, while antagomiR had no effect. Moreover, mitochondrial beta-oxidation and long-chain fatty acid synthesis-related genes were modulated by agomiR addition. Our results demonstrate modulatory roles of miR-100 in BMSC development, lipid deposition, and metabolism and suggest a role of miR-100 in marbling characteristics of meat animals and fat oxidation in muscle.
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31
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Bhamidipati T, Kumar M, Verma SS, Mohanty SK, Kacar S, Reese D, Martinez MM, Kamocka MM, Dunn KW, Sen CK, Singh K. Epigenetic basis of diabetic vasculopathy. Front Endocrinol (Lausanne) 2022; 13:989844. [PMID: 36568089 PMCID: PMC9780391 DOI: 10.3389/fendo.2022.989844] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/21/2022] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) causes peripheral vascular disease because of which several blood-borne factors, including vital nutrients fail to reach the affected tissue. Tissue epigenome is sensitive to chronic hyperglycemia and is known to cause pathogenesis of micro- and macrovascular complications. These vascular complications of T2DM may perpetuate the onset of organ dysfunction. The burden of diabetes is primarily because of a wide range of complications of which nonhealing diabetic ulcers represent a major component. Thus, it is imperative that current research help recognize more effective methods for the diagnosis and management of early vascular injuries. This review addresses the significance of epigenetic processes such as DNA methylation and histone modifications in the evolution of macrovascular and microvascular complications of T2DM.
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Affiliation(s)
- Theja Bhamidipati
- Department of Vascular Surgery, Jefferson-Einstein Medical Center, Philadelphia, PA, United States
| | - Manishekhar Kumar
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sumit S. Verma
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sujit K. Mohanty
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sedat Kacar
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Diamond Reese
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Michelle M. Martinez
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Malgorzata M. Kamocka
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kenneth W. Dunn
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Chandan K. Sen
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
- *Correspondence: Kanhaiya Singh, ; Chandan K. Sen,
| | - Kanhaiya Singh
- Department of Surgery, Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, United States
- *Correspondence: Kanhaiya Singh, ; Chandan K. Sen,
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32
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Díaz del Moral S, Benaouicha M, Muñoz-Chápuli R, Carmona R. The Insulin-like Growth Factor Signalling Pathway in Cardiac Development and Regeneration. Int J Mol Sci 2021; 23:ijms23010234. [PMID: 35008660 PMCID: PMC8745665 DOI: 10.3390/ijms23010234] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/24/2021] [Accepted: 12/24/2021] [Indexed: 12/18/2022] Open
Abstract
Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport and availability. The IGF signalling pathway is essential for cardiac development. IGF2 is the primary mitogen inducing ventricular cardiomyocyte proliferation and morphogenesis of the compact myocardial wall. Conditional deletion of the Igf1r and the insulin receptor (Insr) genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia. The significance of the IGF signalling pathway during embryonic development has led to consider it as a candidate for adult cardiac repair and regeneration. In fact, paracrine IGF2 plays a key role in the transient regenerative ability of the newborn mouse heart. We aimed to review the current knowledge about the role played by the IGF signalling pathway during cardiac development and also the clinical potential of recapitulating this developmental axis in regeneration of the adult heart.
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Affiliation(s)
- Sandra Díaz del Moral
- Institute of Biomedical Research of Málaga (IBIMA), Department of Animal Biology, Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Faculty of Science, University of Málaga, 29071 Malaga, Spain; (S.D.d.M.); (M.B.); (R.M.-C.)
| | - Maha Benaouicha
- Institute of Biomedical Research of Málaga (IBIMA), Department of Animal Biology, Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Faculty of Science, University of Málaga, 29071 Malaga, Spain; (S.D.d.M.); (M.B.); (R.M.-C.)
| | - Ramón Muñoz-Chápuli
- Institute of Biomedical Research of Málaga (IBIMA), Department of Animal Biology, Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Faculty of Science, University of Málaga, 29071 Malaga, Spain; (S.D.d.M.); (M.B.); (R.M.-C.)
| | - Rita Carmona
- Institute of Biomedical Research of Málaga (IBIMA), Department of Animal Biology, Andalusian Center for Nanomedicine and Biotechnology (BIONAND), Faculty of Science, University of Málaga, 29071 Malaga, Spain; (S.D.d.M.); (M.B.); (R.M.-C.)
- Department of Human Anatomy and Embryology, Legal Medicine and History of Medicine, Faculty of Medicine, University of Málaga, 29071 Malaga, Spain
- Correspondence:
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Sanchis-Gomar F, Arnau-Moyano M, Daimiel L, Lippi G, Leischik R, Vallecillo N, Yvert T, Jiménez SL, Santiago C, Pareja-Galeano H. Circulating microRNAs fluctuations in exercise-induced cardiac remodeling: A systematic review. Am J Transl Res 2021; 13:13298-13309. [PMID: 35035676 PMCID: PMC8748080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/30/2021] [Indexed: 06/14/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that participate in gene expression regulation. It has been observed that circulating levels of miRNAs may fluctuate during exercise, showing numerous cardiac biological and physiological effects such as structural and functional adaptations. We aimed to provide an overview of the currently available information concerning the role of circulating miRNAs in cardiovascular adaptations in response to acute and/or chronic exercise training. Relevant studies published were searched in three databases: PubMed, Web of Science and Scopus. A combination of the following keywords was used: ("microRNA" OR "miRNA" OR "miR" AND "exercise" OR "training" OR "physical activity") AND "(heart hypertrophy" OR "cardiac remodeling" OR "cardiac muscle mass" OR "cardiac hypertrophy"). Only experimental studies, written in English and conducted in healthy individuals were included. Five articles met the inclusion criteria and were finally included in this systematic review after reviewing both title, abstract and full-text. A total of thirty-six circulating cardiac-related miRNAs were analyzed, but only five of them (miR-1, miR-133a, miR-146a, miR-206 and miR-221) were directly associated with cardiac adaptations parameters, while two of them (miR-1 and miR-133a) were related to cardiac hypertrophy. Most of them were upregulated immediately after a marathon and returned to basal levels at longer times. Therefore, we conclude that, although evidence is still limited, and long-term studies are needed to obtain more robust evidence, exercise is more likely to affect circulating cardiac-related miRNAs levels.
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Affiliation(s)
- Fabian Sanchis-Gomar
- Department of Physiology, Faculty of Medicine, University of Valencia and INCLIVA Biomedical Research InstituteValencia, Spain
| | | | - Lidia Daimiel
- Nutritional Control of The Epigenome Group, Instituto Madrileño de Estudios Avanzados (IMDEA) Food, CEI UAM+CSICMadrid 28049, Spain
| | - Giuseppe Lippi
- Section of Clinical Biochemistry, University of VeronaVerona, Italy
| | - Roman Leischik
- School of Medicine, Faculty of Health, Witten/Herdecke UniversityWitten, Germany
| | - Néstor Vallecillo
- Faculty of Biomedical and Health Sciences, Universidad Europea de MadridMadrid, Spain
| | - Thomas Yvert
- Faculty of Sport Sciences, Universidad Europea de MadridMadrid, Spain
| | - Sergio L Jiménez
- Centre for Sport Studies, Rey Juan Carlos UniversityMadrid, Spain
| | - Catalina Santiago
- Faculty of Sport Sciences, Universidad Europea de MadridMadrid, Spain
| | - Helios Pareja-Galeano
- Department of Physical Education, Sport and Human Movement, Universidad Autónoma de MadridMadrid, Spain
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Qiu Y, Pan X, Chen Y, Xiao J. Hallmarks of exercised heart. J Mol Cell Cardiol 2021; 164:126-135. [PMID: 34914934 DOI: 10.1016/j.yjmcc.2021.12.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 12/29/2022]
Abstract
The benefits of exercise in humans on the heart have been well recognized for many years. Long-term endurance exercise training can induce physiologic cardiac hypertrophy with normal or enhanced heart function, and provide protective benefits in preventing heart failure. The heart-specific responses that occur during exercise are complex and highly variable. This review mainly focuses on the current understanding of the structural and functional cardiac adaptations to exercise as well as molecular pathways and signaling proteins responsible for these changes. Here, we summarize eight tentative hallmarks that represent common denominators of the exercised heart. These hallmarks are: cardiomyocyte growth, cardiomyocyte fate reprogramming, angiogenesis and lymphangiogenesis, mitochondrial remodeling, epigenetic alteration, enhanced endothelial function, quiescent cardiac fibroblast, and improved cardiac metabolism. A major challenge is to explore the underlying molecular mechanisms for cardio-protective effects of exercise, and to identify therapeutic targets for heart diseases.
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Affiliation(s)
- Yan Qiu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Xue Pan
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Yiwen Chen
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Junjie Xiao
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China; Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China.
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35
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Salamon I, Biagini E, Kunderfranco P, Roncarati R, Ferracin M, Taglieri N, Nardi E, Laprovitera N, Tomasi L, Santostefano M, Ditaranto R, Vitale G, Cavarretta E, Pisani A, Riccio E, Aiello V, Capelli I, La Manna G, Galiè N, Spinelli L, Condorelli G. Circulating miR-184 is a potential predictive biomarker of cardiac damage in Anderson-Fabry disease. Cell Death Dis 2021; 12:1150. [PMID: 34897278 PMCID: PMC8665928 DOI: 10.1038/s41419-021-04438-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 11/17/2021] [Accepted: 11/25/2021] [Indexed: 12/20/2022]
Abstract
Enzyme replacement therapy (ERT) is a mainstay of treatment for Anderson-Fabry disease (AFD), a pathology with negative effects on the heart and kidneys. However, no reliable biomarkers are available to monitor its efficacy. Therefore, we tested a panel of four microRNAs linked with cardiac and renal damage in order to identify a novel biomarker associated with AFD and modulated by ERT. To this end, 60 patients with a definite diagnosis of AFD and on chronic ERT, and 29 age- and sex-matched healthy individuals, were enrolled by two Italian university hospitals. Only miR-184 met both conditions: its level discriminated untreated AFD patients from healthy individuals (c-statistic = 0.7522), and it was upregulated upon ERT (P < 0.001). On multivariable analysis, miR-184 was independently and inversely associated with a higher risk of cardiac damage (odds ratio = 0.86; 95% confidence interval [CI] = 0.76-0.98; P = 0.026). Adding miR-184 to a comprehensive clinical model improved the prediction of cardiac damage in terms of global model fit, calibration, discrimination, and classification accuracy (continuous net reclassification improvement = 0.917, P < 0.001; integrated discrimination improvement [IDI] = 0.105, P = 0.017; relative IDI = 0.221, 95% CI = 0.002-0.356). Thus, miR-184 is a circulating biomarker of AFD that changes after ERT. Assessment of its level in plasma could be clinically valuable in improving the prediction of cardiac damage in AFD patients.
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Affiliation(s)
- Irene Salamon
- Humanitas Research Hospital - IRCCS, 20089, Rozzano, (MI), Italy
- Department of Biomedical Sciences, Humanitas University, 20090, Pieve Emanuele, (MI), Italy
| | - Elena Biagini
- Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | | | - Roberta Roncarati
- Institute of Genetics and Biomedical Research - Milan Unit, National Research Council of Italy, 20089, Rozzano, (MI), Italy
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
| | - Nevio Taglieri
- Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Elena Nardi
- Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
| | - Noemi Laprovitera
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
| | - Luciana Tomasi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
| | - Marisa Santostefano
- Nephrology, Dialysis and Renal Transplant Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Raffaello Ditaranto
- Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
| | - Giovanni Vitale
- Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
| | - Elena Cavarretta
- Department of Medico-Surgical Sciences and Biotechnologies, University of Rome Sapienza, 04100, Latina, Italy
- Mediterranea Cardiocentro, 80122, Naples, Italy
| | - Antonio Pisani
- Department of Public Health - Nephrology Unit, University of Naples Federico II, 80131, Naples, Italy
| | - Eleonora Riccio
- Department of Public Health - Nephrology Unit, University of Naples Federico II, 80131, Naples, Italy
| | - Valeria Aiello
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
- Nephrology, Dialysis and Renal Transplant Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Irene Capelli
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
- Nephrology, Dialysis and Renal Transplant Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Gaetano La Manna
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
- Nephrology, Dialysis and Renal Transplant Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Nazzareno Galiè
- Cardiology Unit, St. Orsola Hospital, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138, Bologna, Italy
| | - Letizia Spinelli
- Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131, Naples, Italy.
| | - Gianluigi Condorelli
- Humanitas Research Hospital - IRCCS, 20089, Rozzano, (MI), Italy.
- Department of Biomedical Sciences, Humanitas University, 20090, Pieve Emanuele, (MI), Italy.
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Liu Q, Deng J, Qiu Y, Gao J, Li J, Guan L, Lee H, Zhou Q, Xiao J. Non-coding RNA basis of muscle atrophy. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:1066-1078. [PMID: 34786211 PMCID: PMC8569427 DOI: 10.1016/j.omtn.2021.10.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Muscle atrophy is a common complication of many chronic diseases including heart failure, cancer cachexia, aging, etc. Unhealthy habits and usage of hormones such as dexamethasone can also lead to muscle atrophy. However, the underlying mechanisms of muscle atrophy are not completely understood. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in muscle atrophy. This review mainly discusses the regulation of ncRNAs in muscle atrophy induced by various factors such as heart failure, cancer cachexia, aging, chronic obstructive pulmonary disease (COPD), peripheral nerve injury (PNI), chronic kidney disease (CKD), unhealthy habits, and usage of hormones; highlights the findings of ncRNAs as common regulators in multiple types of muscle atrophy; and summarizes current therapies and underlying mechanisms for muscle atrophy. This review will deepen the understanding of skeletal muscle biology and provide new strategies and insights into gene therapy for muscle atrophy.
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Affiliation(s)
- Qi Liu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Jiali Deng
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Yan Qiu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Juan Gao
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Jin Li
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Longfei Guan
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China
| | - Hangil Lee
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Qiulian Zhou
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Junjie Xiao
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
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37
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MicroRNAs associated with signaling pathways and exercise adaptation in sarcopenia. Life Sci 2021; 285:119926. [PMID: 34480932 DOI: 10.1016/j.lfs.2021.119926] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 01/06/2023]
Abstract
Considering the expansion of human life-span over the past few decades; sarcopenia, a physiological consequence of aging process characterized with a diminution in mass and strength of skeletal muscle, has become more frequent. Thus, there is a growing need for expanding our knowledge on the molecular mechanisms of muscle atrophy in sarcopenia which are complex and involve many signaling pathways associated with protein degradation and synthesis. MicroRNAs (miRNAs) as evolutionary conserved small RNAs, could complementarily bind to their target mRNAs and post-transcriptionally inhibit their translation. Aberrant expression of miRNAs contributes to the development of sarcopenia by regulating the expression of critical genes involved in age-related skeletal muscle mass loss. Here we have a review on the signaling pathways along with the miRNAs controlling their components expression and subsequently we provide a brief overview on the effects of exercise on expression pattern of miRNAs in sarcopenia.
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38
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Fu C, Huang AH, Galatz LM, Han WM. Cellular and molecular modulation of rotator cuff muscle pathophysiology. J Orthop Res 2021; 39:2310-2322. [PMID: 34553789 DOI: 10.1002/jor.25179] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/04/2021] [Accepted: 09/07/2021] [Indexed: 02/04/2023]
Abstract
Rotator cuff (RC) tendon tears are common shoulder injuries that result in irreversible and persistent degeneration of the associated muscles, which is characterized by severe inflammation, atrophy, fibrosis, and fatty infiltration. Although RC muscle degeneration strongly dictates the overall clinical outcomes, strategies to stimulate RC muscle regeneration have largely been overlooked to date. In this review, we highlight the current understanding of the cellular processes that coordinate muscle regeneration, and the roles of muscle resident cells, including immune cells, fibroadipogenic progenitors, and muscle satellite cells in the pathophysiologic regulation of RC muscles following injury. This review also provides perspectives for potential therapies to alleviate the hallmarks of RC muscle degeneration to address current limitations in postsurgical recovery.
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Affiliation(s)
- Chengcheng Fu
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Alice H Huang
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Department of Orthopedic Surgery, Columbia University, New York City, New York, USA
| | - Leesa M Galatz
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Woojin M Han
- Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York City, New York, USA.,Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
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39
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Bär C, Chatterjee S, Falcão Pires I, Rodrigues P, Sluijter JPG, Boon RA, Nevado RM, Andrés V, Sansonetti M, de Windt L, Ciccarelli M, Hamdani N, Heymans S, Figuinha Videira R, Tocchetti CG, Giacca M, Zacchigna S, Engelhardt S, Dimmeler S, Madonna R, Thum T. Non-coding RNAs: update on mechanisms and therapeutic targets from the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. Cardiovasc Res 2021; 116:1805-1819. [PMID: 32638021 DOI: 10.1093/cvr/cvaa195] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/15/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
Vast parts of mammalian genomes are actively transcribed, predominantly giving rise to non-coding RNA (ncRNA) transcripts including microRNAs, long ncRNAs, and circular RNAs among others. Contrary to previous opinions that most of these RNAs are non-functional molecules, they are now recognized as critical regulators of many physiological and pathological processes including those of the cardiovascular system. The discovery of functional ncRNAs has opened up new research avenues aiming at understanding ncRNA-related disease mechanisms as well as exploiting them as novel therapeutics in cardiovascular therapy. In this review, we give an update on the current progress in ncRNA research, particularly focusing on cardiovascular physiological and disease processes, which are under current investigation at the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. This includes a range of topics such as extracellular vesicle-mediated communication, neurohormonal regulation, inflammation, cardiac remodelling, cardio-oncology as well as cardiac development and regeneration, collectively highlighting the wide-spread involvement and importance of ncRNAs in the cardiovascular system.
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Affiliation(s)
- Christian Bär
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Shambhabi Chatterjee
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Inês Falcão Pires
- Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Patrícia Rodrigues
- Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Joost P G Sluijter
- Experimental Cardiology Laboratory, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Reinier A Boon
- Department of Physiology, Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands.,Institute for Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany.,Partner site Rhein/Main, German Center for Cardiovascular Research (DZHK), Frankfurt am Main, Germany
| | - Rosa M Nevado
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Vicente Andrés
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Marida Sansonetti
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.,Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, The Netherlands.,Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Leon de Windt
- Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, The Netherlands.,Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry, University of Salerno, Italy
| | - Nazha Hamdani
- Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.,Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Stephane Heymans
- Department of Cardiology, Maastricht University Medical Centre, University Hospital Maastricht, The Netherlands.,Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), University Hospital Maastricht, The Netherlands
| | - Raquel Figuinha Videira
- Cardiovascular Research and Development Center, Faculty of Medicine, University of Porto, Porto, Portugal.,Department of Molecular Genetics, Faculty of Science and Engineering, Maastricht University, Maastricht, The Netherlands.,Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Carlo G Tocchetti
- Department of Translational Medical Sciences and Interdepartmental Center of Clinical and Translational Research (CIRCET), Federico II University, Naples, Italy
| | - Mauro Giacca
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.,School of Cardiovascular Medicine & Sciences, King's College London, London, UK.,Department of Medicine, Surgery and Health Sciences, University of Trieste, Italy
| | - Serena Zacchigna
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.,Department of Medicine, Surgery and Health Sciences, University of Trieste, Italy
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Str. 29, Munich 80802, Germany.,DZHK (German Center for Cardiovascular Research), Partner site Munich Heart Alliance, Biedersteiner Str. 29, Munich 80802, Germany
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe University, Germany.,German Center for Cardiovascular Research (DZHK), Frankfurt, Germany.,Cardio-Pulmonary Institute (CPI), Frankfurt, Germany
| | - Rosalinda Madonna
- Institute of Cardiology, University of Pisa, Pisa, Italy.,Department of Internal Medicine, University of Texas Medical School, Houston, TX, USA
| | - Thomas Thum
- Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.,REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
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40
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Li Q, Liu Y, Sun X, Li H, Cheng C, Liu L, Liu F, Zhou Q, Guo C, Tian G, Qie R, Han M, Huang S, Li L, Wang B, Zhao Y, Ren Y, Zhang M, Hu D, Wu J, Lu J. Dose-response association between adult height and all-cause mortality: a systematic review and meta-analysis of cohort studies. Eur J Public Health 2021; 31:652-658. [PMID: 33236090 DOI: 10.1093/eurpub/ckaa213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND We conducted a systematic review and meta-analysis from published cohort studies to examine the association of adult height and all-cause mortality and to further explore the dose-response association. METHODS PubMed, The Cochrane Library, The Ovid, CNKI, CQVIP and Wanfang databases were searched for articles published from database inception to 6 February 2018. We used the DerSimonian-Laird random-effects model to estimate the quantitative association between adult height and all-cause mortality and the restricted cubic splines to model the dose-response association. RESULTS We included 15 articles, with 1 533 438 death events and 2 854 543 study participants. For each 5-cm height increase below the average, the risk of all-cause mortality was reduced by 7% [relative risk (RR) = 0.93, 95% confidence interval (CI), 0.89-0.97] for men and 5% (RR = 0.95, 95% CI, 0.90-0.99) for women. All-cause mortality had a U-shaped association with adult height, the lowest risk occurring at 174 cm for men and 158 cm for women (both Pnonlinearity < 0.001). Relative to the shortest adult height (147 cm for men and 137 cm for women), men at 174 cm had a 47% lower likelihood of all-cause mortality and women at 158 cm a 33% lower risk of all-cause mortality. CONCLUSIONS Our study suggests that the relation between adult height and all-cause mortality is approximately U-shaped in both men and women.
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Affiliation(s)
- Quanman Li
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Yu Liu
- Study Team of Shenzhen's Sanming Project, The Affiliated Luohu Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, People's Republic of China
| | - Xizhuo Sun
- Study Team of Shenzhen's Sanming Project, The Affiliated Luohu Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, People's Republic of China
| | - Honghui Li
- Study Team of Shenzhen's Sanming Project, The Affiliated Luohu Hospital of Shenzhen University Health Science Center, Shenzhen, Guangdong, People's Republic of China
| | - Cheng Cheng
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Leilei Liu
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Feiyan Liu
- Department of Preventive Medicine, Shenzhen University Health Science Center, Shenzhen, Guangdong, People's Republic of China
| | - Qionggui Zhou
- Department of Preventive Medicine, Shenzhen University Health Science Center, Shenzhen, Guangdong, People's Republic of China
| | - Chunmei Guo
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Gang Tian
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Ranran Qie
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Minghui Han
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Shengbing Huang
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Linlin Li
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Bingyuan Wang
- Institute for the Prevention and Treatment of Chronic Non-communicable Diseases, Henan Provincial Center for Disease Control and Prevention, Zhengzhou, Henan, People's Republic of China
| | - Yang Zhao
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Yongcheng Ren
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Ming Zhang
- Department of Preventive Medicine, Shenzhen University Health Science Center, Shenzhen, Guangdong, People's Republic of China
| | - Dongsheng Hu
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Jian Wu
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Jie Lu
- Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People's Republic of China
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Telles GD, Libardi CA, Conceição MS, Vechin FC, Lixandrão ME, DE Andrade ALL, Guedes DN, Ugrinowitsch C, Camera DM. Time Course of Skeletal Muscle miRNA Expression after Resistance, High-Intensity Interval, and Concurrent Exercise. Med Sci Sports Exerc 2021; 53:1708-1718. [PMID: 33731656 DOI: 10.1249/mss.0000000000002632] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Exercise-induced microRNA (miRNA) expression has been implicated in the regulation of skeletal muscle plasticity. However, the specificity and acute time course in miRNA expression after divergent exercise modes are unknown. In a randomized crossover design, we compared the acute expression profile of eight skeletal muscle miRNAs previously reported to be involved in skeletal muscle development, growth, and maintenance after a bout of either resistance exercise (RE), high-intensity interval exercise (HIIE), and concurrent resistance and high-intensity interval exercises (CE). METHODS Nine untrained young men (23.9 ± 2.8 yr, 70.1 ± 14.9 kg, 177.2 ± 3.0 cm, 41.4 ± 5.2 mL·kg-1·min-1) underwent a counterbalanced crossover design in which they performed bouts of RE (2 × 10 repetitions maximum 45° leg press and leg extension exercises), HIEE (12 × 1-min sprints at V˙O2peak with 1-min rest intervals between sprints), and CE (RE followed by HIIE), separated by 1 wk. Vastus lateralis biopsies were harvested immediately before (Pre) and immediately (0 h), 4 h, and 8 h after each exercise bout. RESULTS There were similar increases (main effect of time; P < 0.05) in miR-1-3p, miR-133a-3p, miR-133b, miR-181a-3p, and miR-486 expression at 8 h from Pre with all exercise modes. Besides a main effect of time, miR-23a-3p and miR-206 presented a main effect of condition with lower expression after HIIE compared with RE and CE. CONCLUSIONS Select miRNAs (miR-1-3p, miR-133a-3p, miR-133b, miR-23a-3p, miR-181a-3p, miR-206, miR-486) do not exhibit an expression specificity in the acute recovery period after a single bout of RE, HIIE, or CE in skeletal muscle. Our data also indicate that RE has a higher effect on the expression of miR-23a-3p and miR-206 than HIIE. As upregulation of these miRNAs seems to be confined to the 8-h period after exercise, this may subsequently affect the expression patterns of target mRNAs forming the basis of exercise-induced adaptive responses.
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Affiliation(s)
- Guilherme Defante Telles
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Cleiton Augusto Libardi
- MUSCULAB-Laboratory of Neuromuscular Adaptations to Resistance Training, Department of Physical Education, Federal University of São Carlos-UFSCar, São Carlos, São Paulo, BRAZIL
| | - Miguel Soares Conceição
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Felipe Cassaro Vechin
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Manoel Emílio Lixandrão
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | | | | | - Carlos Ugrinowitsch
- Laboratory of Neuromuscular Adaptations to Strength Training, School of Physical Education and Sport, University of São Paulo (USP), São Paulo, São Paulo, BRAZIL
| | - Donny Michael Camera
- Department of Health and Medical Sciences, Swinburne University, Melbourne, Victoria, AUSTRALIA
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Kesharwani D, Kumar A, Poojary M, Scaria V, Datta M. RNA sequencing reveals potential interacting networks between the altered transcriptome and ncRNome in the skeletal muscle of diabetic mice. Biosci Rep 2021; 41:BSR20210495. [PMID: 34190986 PMCID: PMC8276098 DOI: 10.1042/bsr20210495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/21/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
For a global epidemic like Type 2 diabetes mellitus (T2DM), while impaired gene regulation is identified as a primary cause of aberrant cellular physiology; in the past few years, non-coding RNAs (ncRNAs) have emerged as important regulators of cellular metabolism. However, there are no reports of comprehensive in-depth cross-talk between these regulatory elements and the potential consequences in the skeletal muscle during diabetes. Here, using RNA sequencing, we identified 465 mRNAs and 12 long non-coding RNAs (lncRNAs), to be differentially regulated in the skeletal muscle of diabetic mice and pathway enrichment analysis of these altered transcripts revealed pathways of insulin, FOXO and AMP-activated protein kinase (AMPK) signaling to be majorly over-represented. Construction of networks showed that these pathways significantly interact with each other that might underlie aberrant skeletal muscle metabolism during diabetes. Gene-gene interaction network depicted strong interactions among several differentially expressed genes (DEGs) namely, Prkab2, Irs1, Pfkfb3, Socs2 etc. Seven altered lncRNAs depicted multiple interactions with the altered transcripts, suggesting possible regulatory roles of these lncRNAs. Inverse patterns of expression were observed between several of the deregulated microRNAs (miRNAs) and the differentially expressed transcripts in the tissues. Towards validation, overexpression of miR-381-3p and miR-539-5p in skeletal muscle C2C12 cells significantly decreased the transcript levels of their targets, Nfkbia, Pik3r1 and Pi3kr1, Cdkn2d, respectively. Collectively, the findings provide a comprehensive understanding of the interactions and cross-talk between the ncRNome and transcriptome in the skeletal muscle during diabetes and put forth potential therapeutic options for improving insulin sensitivity.
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Affiliation(s)
- Devesh Kesharwani
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Amit Kumar
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
| | - Mukta Poojary
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
- GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Delhi 110025, India
| | - Vinod Scaria
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
- GN Ramachandran Knowledge Centre for Genome Informatics, CSIR-Institute of Genomics and Integrative Biology, Mathura Road, Delhi 110025, India
| | - Malabika Datta
- CSIR-Institute of Genomics and Integrative Biology, Functional and Genomics Unit, Mall Road, Delhi, India
- Academy of Scientific and Innovative Research, CSIR-HRDC, Kamala Nehru Nagar, Ghaziabad 201002, Uttar Pradesh, India
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Sharma K, Singh P, Amjad Beg M, Dohare R, Athar F, Ali Syed M. Revealing new therapeutic opportunities in hypertension through network-driven integrative genetic analysis and drug target prediction approach. Gene 2021; 801:145856. [PMID: 34293449 DOI: 10.1016/j.gene.2021.145856] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/17/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023]
Abstract
Epidemiological studies have established that untreated hypertension (HTN) is a major independent risk factor for developing cardiovascular diseases (CVD), stroke, renal failure, and other conditions. Several important studies have been published to prevent and manage HTN; however, antihypertensive agents' optimal choice remains controversial. Therefore, the present study is undertaken to update our knowledge in the primary treatment of HTN, specifically in the setting of other three important diseases. MicroRNAs (miRNAs) are remarkably stable short endogenous conserved non-coding RNAs that bind to the mRNA at its (3' UTR) to regulate its gene expression by causing translational repression or mRNA degradation. Through their coordinated activities on different pathways and networks, individual miRNAs control normal and pathological cellular processes. Therefore, to identify the critical miRNA-mRNA-TF interactions, we performed systematic bioinformatics analysis. We have also employed the molecular modelling and docking approach to identify the therapeutic target that delivers novel empathies into Food and Drug Administration approved and herbal drug response physiology. Gene Expression Omnibus (GEO) was employed to identify the differentially expressed genes (DEGs) and hub genes- KNG1, HLA-DPB1, CXCL8, IL1B, and BCL2. The HTN associated feed-forward loop (FFL) network included miR-9-5p, KNG1 and AR. We employed high throughput screening to get the best interacting compounds, telmisartan and limonin, that provided a significant docking score (-13.3 and -12.0 kcal/mol) and a potential protective effect that may help to combat the impact of HTN. The present study provides novel insight into HTN etiology through the identification of mRNAs and miRNAs and associated pathways.
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Affiliation(s)
- Kavita Sharma
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Prithvi Singh
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Md Amjad Beg
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Ravins Dohare
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
| | - Fareeda Athar
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Mansoor Ali Syed
- Translational Research Lab, Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi 110025, India.
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Hassanlou M, Soltani BM, Medlej A, Kay M, Mowla SJ. Hsa-miR-6165 downregulates insulin-like growth factor-1 receptor (IGF-1R) expression and enhances apoptosis in SW480 cells. Biol Chem 2021; 401:477-485. [PMID: 31702994 DOI: 10.1515/hsz-2018-0421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 10/10/2019] [Indexed: 01/06/2023]
Abstract
MicroRNAs are small non-coding RNAs that are implicated in various biological processes. Hsa-miR-6165 (miR-6165), located in the p75NTR gene, is known to induce apoptosis in human cell lines, but its mechanism of action is not fully understood yet. Here, we predicted the insulin-like growth factor 1 receptor (IGF-1R) gene as a bona fide target for miR-6165. The overexpression of miR-6165 in SW480 cells resulted in significant downregulation of IGF-1R expression as detected by real time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Also, it resulted in reduced transcript levels of AKT2, AKT3, PI3KR3, PI3KR5, CCND1, c-MYC and P21 genes detected by RT-qPCR analysis. In addition, a direct interaction between miR-6165 and a 3'UTR sequence of the IGF-1R gene was verified through a dual luciferase assay. Furthermore, miR-6165 and IGF-1R showed opposite patterns of expression during the neural differentiation process of NT2 cells. Annexin V analysis and MTT assay showed that miR-6165 overexpression was followed by increased apoptosis and reduced the viability rate of SW480 cells. Moreover, a lower expression level of miR-6165 was detected in high-grade colorectal tumors compared with low-grade tumors. Taken together, the results of our study suggest a tumor suppressive role of miR-6165 in colorectal cancer, which seems to take place by regulating IGF-1R gene expression.
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Affiliation(s)
- Maryam Hassanlou
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 114-115, Iran
| | - Bahram M Soltani
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 114-115, Iran
| | - Abdallah Medlej
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 114-115, Iran
| | - Maryam Kay
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 114-115, Iran
| | - Seyed Javad Mowla
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 114-115, Iran
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Giagnorio E, Malacarne C, Mantegazza R, Bonanno S, Marcuzzo S. MyomiRs and their multifaceted regulatory roles in muscle homeostasis and amyotrophic lateral sclerosis. J Cell Sci 2021; 134:269129. [PMID: 34137441 DOI: 10.1242/jcs.258349] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of both upper and lower motor neurons (MNs). The main clinical features of ALS are motor function impairment, progressive muscle weakness, muscle atrophy and, ultimately, paralysis. Intrinsic skeletal muscle deterioration plays a crucial role in the disease and contributes to ALS progression. Currently, there are no effective treatments for ALS, highlighting the need to obtain a deeper understanding of the molecular events underlying degeneration of both MNs and muscle tissue, with the aim of developing successful therapies. Muscle tissue is enriched in a group of microRNAs called myomiRs, which are effective regulators of muscle homeostasis, plasticity and myogenesis in both physiological and pathological conditions. After providing an overview of ALS pathophysiology, with a focus on the role of skeletal muscle, we review the current literature on myomiR network dysregulation as a contributing factor to myogenic perturbations and muscle atrophy in ALS. We argue that, in view of their critical regulatory function at the interface between MNs and skeletal muscle fiber, myomiRs are worthy of further investigation as potential molecular targets of therapeutic strategies to improve ALS symptoms and counteract disease progression.
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Affiliation(s)
- Eleonora Giagnorio
- Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.,PhD program in Neuroscience, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Claudia Malacarne
- Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy.,PhD program in Neuroscience, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Renato Mantegazza
- Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy
| | - Silvia Bonanno
- Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy
| | - Stefania Marcuzzo
- Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy
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Bao J, Lu Y, She Q, Dou W, Tang R, Xu X, Zhang M, Zhu L, Zhou Q, Li H, Zhou G, Yang Z, Shi S, Liu Z, Zheng C. MicroRNA-30 regulates left ventricular hypertrophy in chronic kidney disease. JCI Insight 2021; 6:138027. [PMID: 33848263 PMCID: PMC8262338 DOI: 10.1172/jci.insight.138027] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 04/07/2021] [Indexed: 12/04/2022] Open
Abstract
Left ventricular hypertrophy (LVH) is a primary feature of cardiovascular complications in patients with chronic kidney disease (CKD). miRNA-30 is an important posttranscriptional regulator of LVH, but it is unknown whether miRNA-30 participates in the process of CKD-induced LVH. In the present study, we found that CKD not only resulted in LVH but also suppressed miRNA-30 expression in the myocardium. Rescue of cardiomyocyte-specific miRNA-30 attenuated LVH in CKD rats without altering CKD progression. Importantly, in vivo and in vitro knockdown of miRNA-30 in cardiomyocytes led to cardiomyocyte hypertrophy by upregulating the calcineurin signaling directly. Furthermore, CKD-related detrimental factors, such as fibroblast growth factor-23, uremic toxin, angiotensin II, and transforming growth factor–β, suppressed cardiac miRNA-30 expression, while miRNA-30 supplementation blunted cardiomyocyte hypertrophy induced by such factors. These results uncover a potentially novel mechanism of CKD-induced LVH and provide a potential therapeutic target for CKD patients with LVH. Downregulation of myocardial miRNA-30 is involved in chronic kidney disease–induced left ventricular hypertrophy, whereas exogenous miRNA-30 rescue inhibits this process.
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Affiliation(s)
- Jingfu Bao
- National Clinical Research Center of Kidney Diseases, and
| | - Yinghui Lu
- National Clinical Research Center of Kidney Diseases, and
| | - Qinying She
- National Clinical Research Center of Kidney Diseases, and
| | - Weijuan Dou
- National Clinical Research Center of Kidney Diseases, and
| | - Rong Tang
- National Clinical Research Center of Kidney Diseases, and
| | - Xiaodong Xu
- National Clinical Research Center of Kidney Diseases, and
| | - Mingchao Zhang
- National Clinical Research Center of Kidney Diseases, and
| | - Ling Zhu
- National Clinical Research Center of Kidney Diseases, and
| | - Qing Zhou
- Department of Pharmacology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Hui Li
- Department of Pharmacology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Guohua Zhou
- Department of Pharmacology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Zhongzhou Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University School of Medicine, and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China
| | - Shaolin Shi
- National Clinical Research Center of Kidney Diseases, and
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, and
| | - Chunxia Zheng
- National Clinical Research Center of Kidney Diseases, and
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Dual role of miR-1 in the development and function of sinoatrial cells. J Mol Cell Cardiol 2021; 157:104-112. [PMID: 33964276 DOI: 10.1016/j.yjmcc.2021.05.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 04/27/2021] [Accepted: 05/03/2021] [Indexed: 11/20/2022]
Abstract
miR-1, the most abundant miRNA in the heart, modulates expression of several transcription factors and ion channels. Conditions affecting the heart rate, such as endurance training and cardiac diseases, show a concomitant miR-1 up- or down-regulation. Here, we investigated the role of miR-1 overexpression in the development and function of sinoatrial (SAN) cells using murine embryonic stem cells (mESC). We generated mESCs either overexpressing miR-1 and EGFP (miR1OE) or EGFP only (EM). SAN-like cells were selected from differentiating mESC using the CD166 marker. Gene expression and electrophysiological analysis were carried out on both early mES-derived cardiac progenitors and SAN-like cells and on beating neonatal rat ventricular cardiomyocytes (NRVC) over-expressing miR-1. miR1OE cells increased significantly the proportion of CD166+ SAN precursors compared to EM cells (23% vs 12%) and the levels of the transcription factors TBX5 and TBX18, both involved in SAN development. miR1OE SAN-like cells were bradycardic (1,3 vs 2 Hz) compared to EM cells. In agreement with data on native SAN cells, EM SAN-like cardiomyocytes show two populations of cells expressing either slow- or fast-activating If currents; miR1OE SAN-like cells instead have only fast-activating If with a significantly reduced conductance. Western Blot and immunofluorescence analysis showed a reduced HCN4 signal in miR-1OE vs EM CD166+ precursors. Together these data point out to a specific down-regulation of the slow-activating HCN4 subunit by miR-1. Importantly, the rate and If alterations were independent of the developmental effects of miR-1, being similar in NRVC transiently overexpressing miR-1. In conclusion, we demonstrated a dual role of miR-1, during development it controls the proper development of sinoatrial-precursor, while in mature SAN-like cells it modulates the HCN4 pacemaker channel translation and thus the beating rate.
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The Impact of microRNAs in Renin-Angiotensin-System-Induced Cardiac Remodelling. Int J Mol Sci 2021; 22:ijms22094762. [PMID: 33946230 PMCID: PMC8124994 DOI: 10.3390/ijms22094762] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023] Open
Abstract
Current knowledge on the renin-angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets.
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Fa HG, Chang WG, Zhang XJ, Xiao DD, Wang JX. Noncoding RNAs in doxorubicin-induced cardiotoxicity and their potential as biomarkers and therapeutic targets. Acta Pharmacol Sin 2021; 42:499-507. [PMID: 32694762 PMCID: PMC8114921 DOI: 10.1038/s41401-020-0471-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
Anthracyclines, such as doxorubicin (DOX), are well known for their high efficacy in treating multiple cancers, but their clinical usage is limited due to their potential to induce fatal cardiotoxicity. Such detrimental effects significantly impact the overall physical condition or even induce the morbidity and mortality of cancer survivors. Therefore, it is extremely important to understand the mechanisms of DOX-induced cardiotoxicity to develop methods for the early detection of cytotoxicity and therapeutic applications. Studies have shown that many molecular events are involved in DOX-induced cardiotoxicity. However, the precise mechanisms are still not completely understood. Recently, noncoding RNAs (ncRNAs) have been extensively studied in a diverse range of regulatory roles in cellular physiological and pathological processes. With respect to their roles in DOX-induced cardiotoxicity, microRNAs (miRNAs) are the most widely studied, and studies have focused on the regulatory roles of long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), which have been shown to have significant functions in the cardiovascular system. Recent discoveries on the roles of ncRNAs in DOX-induced cardiotoxicity have prompted extensive interest in exploring candidate ncRNAs for utilization as potential therapeutic targets and/or diagnostic biomarkers. This review presents the frontier studies on the roles of ncRNAs in DOX-induced cardiotoxicity, addresses the possibility and prospects of using ncRNAs as diagnostic biomarkers or therapeutic targets, and discusses the possible reasons for related discrepancies and limitations of their use.
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Al-Kafaji G, Al-Muhtaresh HA, Salem AH. Expression and clinical significance of miR-1 and miR-133 in pre-diabetes. Biomed Rep 2021; 14:33. [PMID: 33585035 DOI: 10.3892/br.2021.1409] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 01/22/2021] [Indexed: 12/11/2022] Open
Abstract
Pre-diabetes represents an intermediate state of altered glucose metabolism between normal glucose levels and type 2 diabetes mellitus (T2D), and is considered a significant risk factor for the development of T2D and related complications. Early detection of pre-diabetes may allow for the use of timely and effective treatment strategies to prevent its progression. Circulating microRNAs (miRNAs/miRs) that reflect changes in diabetes-related tissues, including the pancreas, liver, skeletal and heart muscle, and adipose tissue are promising biomarkers of disease progression. In our previous study, it was demonstrated that the cardiac and skeletal muscle specific miR-1 and miR-133 are upregulated in the blood of patients with T2D and cardiovascular disease. Since both miRNAs have been shown to be implicated in insulin resistance, an important feature of pre-diabetes, we hypothesised that their expression may be increased prior to clinical diagnosis of T2D, and may thus serve as biomarkers for pre-diabetes. The expression levels of circulating miRNAs were evaluated by reverse transcription-quantitative PCR in whole blood samples from 55 subjects, including 28 pre-diabetes individuals with impaired fasting glucose (FG) and impaired glucose tolerance, and 27 healthy controls. The individuals with pre-diabetes exhibited significantly higher expression levels of miR-1 and miR-133 compared with the controls (P<0.05). Target prediction search revealed that both miR-1 and miR-133 target several pathways involved in the pathophysiology of diabetes. Pearson's correlation analysis revealed that the two miRNAs were positively correlated with blood glucose parameters, including FG, 2-h oral glucose tolerance test and glycated haemoglobin A1c levels, as well as with insulin resistance (P<0.05). Multivariate logistic regression analysis revealed that the two miRNAs were significantly and directly associated with pre-diabetes, and this association remained significant after adjustment for several confounding variables (P<0.05). Moreover, linear regression analysis showed that the Homeostatic Model Assessment-Insulin Resistance was the only significant predictor to be significantly associated with both miRNAs (P<0.05). In discriminating pre-diabetes individuals from healthy controls, the area under the curves (AUCs) of the receiver operating characteristic curves (ROCs) were 0.813 and 0.810 for miR-1 and miR-133 respectively (P<0.05). Despite the relatively small number of participants, the present study showed for the first time that circulating levels of miR-1 and miR-133 were increased in individuals with pre-diabetes, and they were associated with important features of pre-diabetes. Thus, they may serve as clinical biomarkers for the early-stages of T2D.
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Affiliation(s)
- Ghada Al-Kafaji
- Department of Molecular Medicine/Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain
| | - Haifa Abdulla Al-Muhtaresh
- Department of Molecular Medicine/Al-Jawhara Centre for Molecular Medicine, Genetics, and Inherited Disorders, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain
| | - Abdel Halim Salem
- Department of Anatomy, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 26671, Kingdom of Bahrain
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