bims-mimead 2024-10-06 papers

bims-mimead

Biomed News

on Mitochondrial metabolism in ageing and metabolic disease

Issue of 2024‒10‒06
fifteen papers selected by
Rachel M. Handy, University of Guelph

Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.
p38α kinase governs muscle strength through PGC1α in mice.
The mitochondrial Na+/Ca2+ exchanger NCLX is implied in the activation of hypoxia-inducible factors.
Beta2-Adrenergic Stimulation Induces Resistance Training-Like Adaptations in Human Skeletal Muscle: Potential Role of KLHL41.
Role of epicardial adipose tissue in cardiac remodeling.
Temporal alterations of the nascent proteome in response to mitochondrial stress.
Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases.
Hypoxia signaling in the adipose tissue.
Mitochondria: the beating heart of the eukaryotic cell.
Exosomal miRNAs and isomiRs: potential biomarkers for type 2 diabetes mellitus.
Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.
Improving effect of physical exercise on heart failure: Reducing oxidative stress-induced inflammation by restoring Ca2+ homeostasis.
Mechanisms and regulation of substrate degradation by the 26S proteasome.
Dissecting human adipose tissue heterogeneity using single-cell omics technologies.
Contractile Effects of Semaglutide in the Human Atrium.

Clin Proteomics. 2024 Sep 30. 21(1): 57

Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.

Andrea Ramirez-Sagredo, Anju Teresa Sunny, Kellye A Cupp-Sutton, Trishika Chowdhury, Zhitao Zhao, Si Wu, Ying Ann Chiao.

  BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the prevalence of CVDs increases markedly with age. Due to the high energetic demand, the heart is highly sensitive to mitochondrial dysfunction. The complexity of the cardiac mitochondrial proteome hinders the development of effective strategies that target mitochondrial dysfunction in CVDs. Mammalian mitochondria are composed of over 1000 proteins, most of which can undergo post-translational modifications (PTMs). Top-down proteomics is a powerful technique for characterizing and quantifying proteoform sequence variations and PTMs. However, there are still knowledge gaps in the study of age-related mitochondrial proteoform changes using this technique. In this study, we used top-down proteomics to identify intact mitochondrial proteoforms in young and old hearts and determined changes in protein abundance and PTMs in cardiac aging.METHODS: Intact mitochondria were isolated from the hearts of young (4-month-old) and old (24-25-month-old) mice. The mitochondria were lysed, and mitochondrial lysates were subjected to denaturation, reduction, and alkylation. For quantitative top-down analysis, there were 12 runs in total arising from 3 biological replicates in two conditions, with technical duplicates for each sample. The collected top-down datasets were deconvoluted and quantified, and then the proteoforms were identified.
RESULTS: From a total of 12 LC-MS/MS runs, we identified 134 unique mitochondrial proteins in the different sub-mitochondrial compartments (OMM, IMS, IMM, matrix). 823 unique proteoforms in different mass ranges were identified. Compared to cardiac mitochondria of young mice, 7 proteoforms exhibited increased abundance and 13 proteoforms exhibited decreased abundance in cardiac mitochondria of old mice. Our analysis also detected PTMs of mitochondrial proteoforms, including N-terminal acetylation, lysine succinylation, lysine acetylation, oxidation, and phosphorylation. Data are available via ProteomeXchange with the identifier PXD051505.
CONCLUSION: By combining mitochondrial protein enrichment using mitochondrial fractionation with quantitative top-down analysis using ultrahigh-pressure liquid chromatography (UPLC)-MS and label-free quantitation, we successfully identified and quantified intact proteoforms in the complex mitochondrial proteome. Using this approach, we detected age-related changes in abundance and PTMs of mitochondrial proteoforms in the heart.

Keywords:  Cardiac aging; Label-free quantitation; Mitochondria; Post-translational modifications; Top-down proteomics

DOI:  https://doi.org/10.1186/s12014-024-09509-1
Acta Physiol (Oxf). 2024 Oct 03. e14234

p38α kinase governs muscle strength through PGC1α in mice.

Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A Dumesic, Sarah E Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M Spiegelman, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio.

  AIMS: Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.METHODS: We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.
RESULTS: Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.
CONCLUSIONS: This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; muscle strength; p38α; skeletal muscle

DOI:  https://doi.org/10.1111/apha.14234
Redox Biol. 2024 Sep 19. pii: S2213-2317(24)00342-2. [Epub ahead of print]77 103364

The mitochondrial Na+/Ca2+ exchanger NCLX is implied in the activation of hypoxia-inducible factors.

Carmen Choya-Foces, Elisa Navarro, Cristóbal de Los Ríos, Manuela G López, Javier Egea, Pablo Hernansanz-Agustín, Antonio Martínez-Ruiz.

Eukaryotic cells and organisms depend on oxygen for basic living functions, and they display a panoply of adaptations to situations in which oxygen availability is diminished (hypoxia). A number of these responses in animals are mediated by changes in gene expression programs directed by hypoxia-inducible factors (HIFs), whose main mechanism of stabilization and functional activation in response to decreased cytosolic oxygen concentration was elucidated two decades ago. Human acute responses to hypoxia have been known for decades, although their precise molecular mechanism for oxygen sensing is not fully understood. It is already known that a redox component, linked with reactive oxygen species (ROS) production of mitochondrial origin, is implied in these responses. We have recently described a mechanism by which the mitochondrial sodium/calcium exchanger, NCLX, participates in mitochondrial electron transport chain regulation and ROS production in response to acute hypoxia. Here we show that NCLX is also implied in the response to hypoxia mediated by the HIFs. By using a NCLX inhibitor and interference RNA we show that NCLX activity is necessary for HIF-α subunits stabilization in hypoxia and for HIF-1-dependent transcriptional activity. We also show that hypoxic mitochondrial ROS production is not required for HIF-1α stabilization under all circumstances, suggesting that the basal cytosolic redox state or other mechanism(s) could be operating in the NCLX-mediated response to hypoxia that operates through HIF-α stabilization. This finding provides a link between acute and medium-term responses to hypoxia, reinforcing a central role of mitochondrial cell signalling in the response to hypoxia.

DOI: https://doi.org/10.1016/j.redox.2024.103364
Scand J Med Sci Sports. 2024 Oct;34(10): e14736

Beta2-Adrenergic Stimulation Induces Resistance Training-Like Adaptations in Human Skeletal Muscle: Potential Role of KLHL41.

Søren Jessen, Júlia Prats Quesada, Andrea Di Credico, Roger Moreno-Justicia, Richard Wilson, Glenn Jacobson, Jens Bangsbo, Atul S Deshmukh, Morten Hostrup.

  Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistance training impractical. The beta2-adrenergic receptor has been highlighted as a potential target to promote muscle hypertrophy and treat atrophic conditions. Here, we investigate the proteomic changes associated with beta2-adrenergic-mediated muscle hypertrophy, using resistance training as a hypertrophic comparator. We utilize MS-based proteomics to map skeletal muscle proteome remodeling in response to beta2-adrenergic stimulation or resistance training as well as cell model validation. We report that beta2-adrenergic stimulation mimics multiple features of resistance training in proteome-wide remodeling, comprising systematic upregulation of ribosomal subunits and concomitant downregulation of mitochondrial proteins. Approximately 20% of proteins were regulated in both conditions, comprising proteins involved in steroid metabolism (AKR1C1, AKR1C2, AKRC1C3), protein-folding (SERPINB1), and extracellular matrix organization (COL1A1, COL1A2). Among overall most significantly upregulated proteins were kelch-like family members (KLHL) 40 and 41. In follow-up experiments, we identify KLHL41 as having novel implications for beta2-adrenergic-mediated muscle hypertrophy. Treating C2C12 cells with beta2-agonist for 96 h increased myotube diameter by 48% (p < 0.001). This anabolic effect was abolished by prior knockdown of KLHL41. Using siRNA, KLHL41 abundance was decreased by 60%, and the anabolic response to beta2-agonist was diminished (+ 15%, i.e., greater in the presence of KLHL41, knock-down × treatment: p = 0.004). In conclusion, protein-wide remodeling induced by beta2-adrenergic stimulation mimics multiple features of resistance training, and thus the beta2-adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load.

Keywords:  atrophy; kelch‐like; muscle hypertrophy; strength training; target

DOI:  https://doi.org/10.1111/sms.14736
Diabetes Res Clin Pract. 2024 Oct 02. pii: S0168-8227(24)00788-5. [Epub ahead of print] 111878

Role of epicardial adipose tissue in cardiac remodeling.

Rongjun Zou, Miao Zhang, Weihui Lv, Jun Ren, Xiaoping Fan.

  Epicardial adipose tissue, or epicardial fat, is a type of visceral fat located between the heart and the pericardium. Due to its anatomical proximity to the heart, EAT plays a significant role in both cardiac physiology and pathologies, including cardiac remodeling and cardiovascular diseases (CVD). However, our understanding of how EAT pathology is influenced by risk factors such as obesity and type 2 diabetes mellitus and how altered EAT can drive cardiac remodeling and CVD, remains limited. Herein, we aimed to summarize and discuss the latest findings on EAT and its role in cardiac remodeling, highlighting the outcomes of clinical and observational studies, provide mechanistic insights, and finally introduce emerging therapeutic agents and nutritional guidelines aimed at preventing these conditions.

Keywords:  And adipocytokines; Cardiac remodeling; Cardiovascular diseases; Diabetes; Epicardial fat/adipose tissue; Leptin; Obesity

DOI:  https://doi.org/10.1016/j.diabres.2024.111878
Cell Rep. 2024 Oct 02. pii: S2211-1247(24)01154-9. [Epub ahead of print]43(10): 114803

Temporal alterations of the nascent proteome in response to mitochondrial stress.

Tomasz M Stępkowski, Vanessa Linke, Dorota Stadnik, Maciej Zakrzewski, Anna E Zawada, Remigiusz A Serwa, Agnieszka Chacinska.

  Under stress, protein synthesis is attenuated to preserve energy and mitigate challenges to protein homeostasis. Here, we describe, with high temporal resolution, the dynamic landscape of changes in the abundance of proteins synthesized upon stress from transient mitochondrial inner membrane depolarization. This nascent proteome was altered when global translation was attenuated by stress and began to normalize as translation was recovering. This transition was associated with a transient desynchronization of cytosolic and mitochondrial translation and recovery of cytosolic and mitochondrial ribosomal proteins. Further, the elongation factor EEF1A1 was downregulated upon mitochondrial stress, and its silencing mimicked the stress-induced nascent proteome remodeling, including alterations in the nascent respiratory chain proteins. Unexpectedly, the stress-induced alterations in the nascent proteome were independent of physiological protein abundance and turnover. In summary, we provide insights into the physiological and pathological consequences of mitochondrial function and dysfunction.

Keywords:  CP: Cell biology; CP: Metabolism; EEF1A; EEF1A1; cellular stress; elongation factor; mass spectrometry; mitochondria; nascent chain; protein synthesis; proteomics; translation

DOI:  https://doi.org/10.1016/j.celrep.2024.114803
Biomedicines. 2024 Sep 19. pii: 2129. [Epub ahead of print]12(9):

Adipokines in the Crosstalk between Adipose Tissues and Other Organs: Implications in Cardiometabolic Diseases.

Shaghayegh Hemat Jouy, Sukrutha Mohan, Giorgia Scichilone, Amro Mostafa, Abeer M Mahmoud.

  Adipose tissue was previously regarded as a dormant organ for lipid storage until the identification of adiponectin and leptin in the early 1990s. This revelation unveiled the dynamic endocrine function of adipose tissue, which has expanded further. Adipose tissue has emerged in recent decades as a multifunctional organ that plays a significant role in energy metabolism and homeostasis. Currently, it is evident that adipose tissue primarily performs its function by secreting a diverse array of signaling molecules known as adipokines. Apart from their pivotal function in energy expenditure and metabolism regulation, these adipokines exert significant influence over a multitude of biological processes, including but not limited to inflammation, thermoregulation, immune response, vascular function, and insulin sensitivity. Adipokines are pivotal in regulating numerous biological processes within adipose tissue and facilitating communication between adipose tissue and various organs, including the brain, gut, pancreas, endothelial cells, liver, muscle, and more. Dysregulated adipokines have been implicated in several metabolic diseases, like obesity and diabetes, as well as cardiovascular diseases. In this article, we attempted to describe the significance of adipokines in developing metabolic and cardiovascular diseases and highlight their role in the crosstalk between adipose tissues and other tissues and organs.

Keywords:  adipokines; adipose tissue; cardiovascular; crosstalk; diabetes; inflammation; insulin resistance; metabolism; obesity

DOI:  https://doi.org/10.3390/biomedicines12092129
J Mol Cell Biol. 2024 Oct 03. pii: mjae039. [Epub ahead of print]

Hypoxia signaling in the adipose tissue.

Phu M Huynh, Fenfen Wang, Yu A An.

  Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in human and rodent models of obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.

Keywords:  adipose tissue; hypoxia; hypoxia-inducible factor; obesity

DOI:  https://doi.org/10.1093/jmcb/mjae039
FEBS Open Bio. 2024 Oct;14(10): 1588-1590

Mitochondria: the beating heart of the eukaryotic cell.

Johannes M Herrmann.

Mitochondria are essential organelles of eukaryotic cells. They consist of hundreds of proteins, which are synthesized in the cytosol and imported into mitochondria via different targeting routes. In addition, a small number of proteins are encoded by the organellar genome and synthesized by mitochondrial ribosomes. In this 'In the Limelight' special issue of FEBS Open Bio, five review articles describe these different biogenesis routes of mitochondrial proteins and provide a comprehensive overview of the structures and mechanisms by which mitochondrial proteins are synthesized and transported to their respective location within the organelle. These reviews, written by leading experts, provide a general overview, but also highlight current developments in the field of mitochondrial biogenesis.

DOI: https://doi.org/10.1002/2211-5463.13884
Precis Clin Med. 2024 Sep;7(3): pbae021

Exosomal miRNAs and isomiRs: potential biomarkers for type 2 diabetes mellitus.

Yong Ling Sou, William M Chilian, Wickneswari Ratnam, Shamsul Mohd Zain, Sharifah Zamiah Syed Abdul Kadir, Yan Pan, Yuh-Fen Pung.

  Type 2 diabetes mellitus (T2DM) is a metabolic disease that is characterized by chronic hyperglycaemia. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play important roles in post-transcriptional gene regulation. They are negative regulators of their target messenger RNAs (mRNAs), in which they bind either to inhibit mRNA translation, or to induce mRNA decay. Similar to proteins, miRNAs exist in different isoforms (isomiRs). miRNAs and isomiRs are selectively loaded into small extracellular vesicles, such as the exosomes, to protect them from RNase degradation. In T2DM, exosomal miRNAs produced by different cell types are transported among the primary sites of insulin action. These interorgan crosstalk regulate various T2DM-associated pathways such as adipocyte inflammation, insulin signalling, and β cells dysfunction among many others. In this review, we first focus on the mechanism of exosome biogenesis, followed by miRNA biogenesis and isomiR formation. Next, we discuss the roles of exosomal miRNAs and isomiRs in the development of T2DM and provide evidence from clinical studies to support their potential roles as T2DM biomarkers. Lastly, we highlight the use of exosomal miRNAs and isomiRs in personalized medicine, as well as addressing the current challenges and future opportunities in this field. This review summarizes how research on exosomal miRNAs and isomiRs has developed from the very basic to clinical applications, with the goal of advancing towards the era of personalized medicine.

Keywords:  extracellular vesicles; hyperglycaemia; insulin resistance; obesity; precision medicine

DOI:  https://doi.org/10.1093/pcmedi/pbae021
Int J Mol Sci. 2024 Sep 11. pii: 9802. [Epub ahead of print]25(18):

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.

Maria Mirabelli, Roberta Misiti, Luciana Sicilia, Francesco S Brunetti, Eusebio Chiefari, Antonio Brunetti, Daniela P Foti.

  Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

Keywords:  adipokine; adipose tissue; hypoxia; inflammation; insulin resistance; micro-RNA

DOI:  https://doi.org/10.3390/ijms25189802
Mol Cell Biochem. 2024 Oct 04.

Improving effect of physical exercise on heart failure: Reducing oxidative stress-induced inflammation by restoring Ca2+ homeostasis.

Shunling Yuan, Zhongkai Kuai, Fei Zhao, Diqun Xu, Weijia Wu.

  Heart failure (HF) is associated with the occurrence of mitochondrial dysfunction. ATP produced by mitochondria through the tricarboxylic acid cycle is the main source of energy for the heart. Excessive release of Ca2+ from myocardial sarcoplasmic reticulum (SR) in HF leads to excessive Ca2+ entering mitochondria, which leads to mitochondrial dysfunction and REDOX imbalance. Excessive accumulation of ROS leads to mitochondrial structure damage, which cannot produce and provide energy. In addition, the accumulation of a large number of ROS can activate NF-κB, leading to myocardial inflammation. Energy deficit in the myocardium has long been considered to be the main mechanism connecting mitochondrial dysfunction and systolic failure. However, exercise can improve the Ca2+ imbalance in HF and restore the Ca2+ disorder in mitochondria. Similarly, exercise activates mitochondrial dynamics to improve mitochondrial function and reshape intact mitochondrial structure, rebalance mitochondrial REDOX, reduce excessive release of ROS, and rescue cardiomyocyte energy failure in HF. In this review, we summarize recent evidence that exercise can improve Ca2+ homeostasis in the SR and activate mitochondrial dynamics, improve mitochondrial function, and reduce oxidative stress levels in HF patients, thereby reducing chronic inflammation in HF patients. The improvement of mitochondrial dynamics is beneficial for ameliorating metabolic flow bottlenecks, REDOX imbalance, ROS balance, impaired mitochondrial Ca2+ homeostasis, and inflammation. Interpretation of these findings will lead to new approaches to disease mechanisms and treatment.

Keywords:  Ca2+ ; Exercise; Heart failure; Mitochondrial dynamics; ROS

DOI:  https://doi.org/10.1007/s11010-024-05124-8
Nat Rev Mol Cell Biol. 2024 Oct 03.

Mechanisms and regulation of substrate degradation by the 26S proteasome.

Connor Arkinson, Ken C Dong, Christine L Gee, Andreas Martin.

The 26S proteasome is involved in degrading and regulating the majority of proteins in eukaryotic cells, which requires a sophisticated balance of specificity and promiscuity. In this Review, we discuss the principles that underly substrate recognition and ATP-dependent degradation by the proteasome. We focus on recent insights into the mechanisms of conventional ubiquitin-dependent and ubiquitin-independent protein turnover, and discuss the plethora of modulators for proteasome function, including substrate-delivering cofactors, ubiquitin ligases and deubiquitinases that enable the targeting of a highly diverse substrate pool. Furthermore, we summarize recent progress in our understanding of substrate processing upstream of the 26S proteasome by the p97 protein unfoldase. The advances in our knowledge of proteasome structure, function and regulation also inform new strategies for specific inhibition or harnessing the degradation capabilities of the proteasome for the treatment of human diseases, for instance, by using proteolysis targeting chimera molecules or molecular glues.

DOI: https://doi.org/10.1038/s41580-024-00778-0
Stem Cell Res Ther. 2024 Sep 27. 15(1): 322

Dissecting human adipose tissue heterogeneity using single-cell omics technologies.

Giuliana Di Rocco, Angelo Trivisonno, Giovanni Trivisonno, Gabriele Toietta.

  Single-cell omics technologies that profile genes (genomic and epigenomic) and determine the abundance of mRNA (transcriptomic), protein (proteomic and secretomic), lipids (lipidomic), and extracellular matrix (matrisomic) support the dissection of adipose tissue heterogeneity at unprecedented resolution in a temporally and spatially defined manner. In particular, cell omics technologies may provide innovative biomarkers for the identification of rare specific progenitor cell subpopulations, assess transcriptional and proteomic changes affecting cell proliferation and immunomodulatory potential, and accurately define the lineage hierarchy and differentiation status of progenitor cells. Unraveling adipose tissue complexity may also provide for the precise assessment of a dysfunctional state, which has been associated with cancer, as cancer-associated adipocytes play an important role in shaping the tumor microenvironment supporting tumor progression and metastasis, obesity, metabolic syndrome, and type 2 diabetes mellitus. The information collected by single-cell omics has relevant implications for regenerative medicine because adipose tissue is an accessible source of multipotent cells; alternative cell-free approaches, including the use of adipose tissue stromal cell-conditioned medium, extracellular vesicles, or decellularized extracellular matrix, are clinically valid options. Subcutaneous white adipose tissue, which is generally harvested via liposuction, is highly heterogeneous because of intrinsic biological variability and extrinsic inconsistencies in the harvesting and processing procedures. The current limited understanding of adipose tissue heterogeneity impinges on the definition of quality standards appropriate for clinical translation, which requires consistency and uniformity of the administered product. We review the methods used for dissecting adipose tissue heterogeneity and provide an overview of advances in omics technology that may contribute to the exploration of heterogeneity and dynamics of adipose tissue at the single-cell level.

Keywords:  Adipose tissue; Omics technologies; Regenerative medicine; Single-cell sequencing; Tissue heterogeneity

DOI:  https://doi.org/10.1186/s13287-024-03931-w
Pharmaceutics. 2024 Aug 28. pii: 1139. [Epub ahead of print]16(9):

Contractile Effects of Semaglutide in the Human Atrium.

Joachim Neumann, Katarína Hadová, Jan Klimas, Britt Hofmann, Ulrich Gergs.

  Semaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. GLP-1R agonists are used to treat type 2 diabetes and obesity. It is currently unknown whether semaglutide can directly increase force of contraction (FOC) in the human heart. We tested the hypothesis that semaglutide might increase the FOC in the isolated human atrium. To this end, we conducted contraction experiments in isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery. We detected a concentration- and time-dependent positive inotropic effect (PIE) of semaglutide in HAP. These PIEs were accompanied by increases in the rates of tension development and tension relaxation and a reduction in muscle relaxation time. The PIE of semaglutide in HAP was attenuated by H89, an inhibitor of the cyclic AMP-dependent protein kinase and by ryanodine, an inhibitor of sarcoplasmic Ca2+ release. Semaglutide up to 100 nM failed to exert a PIE in isolated electrically paced (1 Hz) wild-type mouse left atrial preparations studied for comparison. Our data suggest that semaglutide can increase the FOC in the atria of patients at therapeutic drug concentrations.

Keywords:  GLP-1 receptor; human atrium; inotropy; semaglutide

DOI:  https://doi.org/10.3390/pharmaceutics16091139