Search Results (138)

Skeletal muscle regeneration depends on muscle stem cells, which give rise to myoblasts that drive muscle growth, repair, and maintenance. In bats—the only mammals capable of powered flight—these processes must also sustain contractile performance under extreme mechanical and metabolic stress. However, the cellular and molecular mechanisms underlying bat muscle physiology remain largely unknown. To enable mechanistic investigation of these traits, we established the first myoblast cell lines from the pectoralis muscle of Pteronotus mesoamericanus, a highly maneuverable aerial insectivore. Using both spontaneous immortalization and exogenous hTERT/CDK4 gene overexpression, we generated two stable cell lines that retain proliferative capacity and differentiate into contractile myotubes. These cells exhibit frequent spontaneous contractions, suggesting robust functional integrity at the neuromuscular junction. In parallel, we performed transcriptomic and metabolic profiling of native pectoralis tissue in the closely related Pteronotus parnellii to define molecular programs supporting muscle specialization. Gene expression analyses revealed enriched pathways for muscle metabolism, development, and regeneration, highlighting supporting roles in tissue maintenance and repair. Consistent with this profile, the flight muscle is triglyceride-rich, which serves as an important fuel source for energetically demanding processes, including muscle contraction and cellular recovery. Integration of transcriptomic and metabolic data identified three key metabolic modules—glucose utilization, lipid handling, and nutrient signaling—that likely coordinate ATP production and support metabolic flexibility. Together, these complementary tools and datasets provide the first in vitro platform for investigating bat muscle research, enabling direct exploration of muscle regeneration, metabolic resilience, and evolutionary physiology. Full article

Pancreatic cancer is frequently accompanied by cancer-associated cachexia, a debilitating metabolic syndrome marked by progressive skeletal muscle wasting and systemic metabolic dysfunction. This study presents a systems biology framework to simultaneously identify therapeutic targets for both pancreatic ductal adenocarcinoma (PDAC) and its associated cachexia (PDAC-CX), using cell-specific genome-scale metabolic models (GSMMs). The human metabolic network Recon3D was extended to include protein synthesis, degradation, and recycling pathways for key inflammatory and structural proteins. These enhancements enabled the reconstruction of cell-specific GSMMs for PDAC and PDAC-CX, and their respective healthy counterparts, based on transcriptomic datasets. Medium-independent metabolic biomarkers were identified through Parsimonious Metabolite Flow Variability Analysis and differential expression analysis across five nutritional conditions. A fuzzy multi-objective optimization framework was employed within the anticancer target discovery platform to evaluate cell viability and metabolic deviation as dual criteria for assessing therapeutic efficacy and potential side effects. While single-enzyme targets were found to be context-specific and medium-dependent, eight combinatorial targets demonstrated robust, medium-independent effects in both PDAC and PDAC-CX cells. These include the knockout of SLC29A2, SGMS1, CRLS1, and the RNF20–RNF40 complex, alongside upregulation of CERK and PIKFYVE. The proposed integrative strategy offers novel therapeutic avenues that address both tumor progression and cancer-associated cachexia, with improved specificity and reduced off-target effects, thereby contributing to translational oncology. Full article

The electrodynamics of current provide much of our technology, from telegraphs to the wired infrastructure powering the circuits of our electronic technology. Current flow is analyzed by its own rules that involve the Maxwell Ampere law and magnetism. Electrostatics does not involve magnetism, and so current flow and electrodynamics cannot be derived from electrostatics. Practical considerations also prevent current flow from being analyzed one charge at a time. There are too many charges, and far too many interactions to allow computation. Current flow is essential in biology. Currents are carried by electrons in mitochondria in an electron transport chain. Currents are carried by ions in nerve and muscle cells. Currents everywhere follow the rules of current flow: Kirchhoff’s current law and its generalizations. The importance of electron and proton flows in generating ATP was discovered long ago but they were not analyzed as electrical currents. The flow of protons and transport of electrons form circuits that must be analyzed by Kirchhoff’s law. A chemiosmotic theory that ignores the laws of current flow is incorrect physics. Circuit analysis is easily applied to short systems like mitochondria that have just one internal electrical potential in the form of the Hodgkin Huxley Katz (HHK) equation. The HHK equation combined with classical descriptions of chemical reactions forms a computable model of cytochrome c oxidase, part of the electron transport chain. The proton motive force is included as just one of the components of the total electrochemical potential. Circuit analysis includes its role just as it includes the role of any other ionic current. Current laws are now needed to analyze the flow of electrons and protons, as they generate ATP in mitochondria and chloroplasts. Chemiosmotic theory must be replaced by an electro-osmotic theory of ATP production that conforms to the Maxwell Ampere equation of electrodynamics while including proton movement and the proton motive force. Full article

Abdominal aortic aneurysm (AAA) is the most common aortic disease occurring below the renal arteries, caused by multiple etiologies. Currently, no effective drug treatment exists, and the specific pathogenesis remains unclear. Due to its insidious onset and diagnostic challenges, AAA often culminates in aortic rupture, which has a high mortality rate. During AAA development, vascular smooth muscle cells (VSMCs) undergo significant pathological alterations, including contractile dysfunction, phenotypic modulation, cellular degradation, and heightened inflammatory and oxidative stress responses. In particular, emerging evidence implicates vascular smooth muscle cell (VSMC) metabolic dysregulation and mitochondrial dysfunction as key contributors to AAA progression. In this review, we systematically summarize the current understanding of VSMC biology, including their developmental origins, structural characteristics, and functional roles in aortic wall homeostasis, along with the regulatory networks governing the VSMC phenotype and functional maintenance. This review highlights the urgent need for further investigation into the aortic wall VSMC pathophysiology to identify novel therapeutic targets for AAA. These insights may pave the way for innovative treatment strategies in aortic disease management. Full article

Donkeys (Equus asinus) hold significant agricultural value in China, particularly for their hides and meat, which possess notable medicinal and dietary importance. However, their reproductive efficiency remains suboptimal compared with other livestock. Ovarian function is a key determinant of fertility, yet the molecular mechanisms underlying donkey ovarian biology remain largely unexplored. To address this gap, we performed single-cell RNA sequencing of donkey ovaries, generating a high-resolution transcriptomic atlas comprising 17,423 cells. Cross-species comparative analysis revealed a high degree of evolutionary conservation in core ovarian cell types, including endothelial, epithelial, immune, and smooth muscle cells, among vertebrates. In contrast, granulosa and theca cells exhibited distinct transcriptional profiles across species, reflecting lineage-specific adaptations. Notably, we identified key genes with donkey-specific expression patterns, including NR3C1 in endothelial cells, LIPE in granulosa cells, and DHRS9 in theca interna cells. Furthermore, an in vitro cumulus–oocyte complex model demonstrated the critical role of GATM in mammalian oocyte maturation. Collectively, these findings provide a comprehensive characterization of ovarian cell-type conservation and species-specific adaptations, offering key molecular insights into the mechanisms underlying cross-species differences in reproductive efficiency. Full article

In recent years, the field of skeletal muscle tissue engineering has experienced significant advancements, evolving from traditional two-dimensional (2D) cell cultures to increasingly sophisticated three-dimensional (3D) engineered constructs. While 2D models have provided foundational insights into muscle cell biology, emerging 3D platforms aim to better recapitulate the complex native muscle environment, including mature muscle fibers, supportive vasculature, and native-like extracellular matrix (ECM) composition. Here, we provide a comprehensive review of current in vitro skeletal muscle models, detailing their design principles, structure, and functionalities as well as the advantages and limitations inherent to each approach. We put a special emphasis on 3D engineered muscle tissues (EMTs) developed through advanced bioengineering strategies and note that design criteria such as scaffold selection, perfusion system incorporation, and co-culture with supporting cell types have significantly enhanced tissue maturity and complexity. Lastly, we explore the application of these engineered models to disease studies, highlighting models of both mendelian muscle disorders and common polygenic diseases and the potential of these platforms for drug discovery and regenerative therapies. Although an ideal in vitro model that fully recapitulates native muscular architecture, vascularization, and ECM complexity is yet to be realized, we identify current challenges and propose future directions for advancing these bioengineered systems. By integrating fundamental design criteria with emerging technologies, this review provides a roadmap for next-generation skeletal muscle models poised to deepen our understanding of muscle biology and accelerate therapeutic innovation. Full article

During mouse pregnancy, the pubic symphysis (PS) undergoes a gradual transitioning into an interpubic ligament (IpL) for a successful delivery. After birth, this IpL is rapidly remodeled, returning to the non-pregnant morphology. The PS fibrocartilaginous cells acquire a myofibroblast-like phenotype, characterized by extracellular matrix (ECM) secretion, expression of α-smooth muscle actin (α-SMA), and vimentin. While the presence of myofibroblast-like cells during the IpL remodeling is well described, cell–cell interactions and how this might contribute to the delivery remains poorly understood. This study uses ultrastructure and molecular approaches to investigate cell–cell and cell–ECM junctions during mouse pregnancy and postpartum. Our findings reveal that the intercellular contacts between adjacent IpL myofibroblast-like cells, particularly at late pregnancy stages, are characterized as adherens and GAP junctions. The acquisition of contractile elements by IpL cells, coupled with neighboring cells and the surrounding ECM via junctional complexes, suggests an important role in supporting changes in the mechanical forces generated by pubic bone movements during mouse pregnancy and also in tying the pelvic bones together, which may help the birth canal closure after delivery. Further studies in PS biology may investigate fibroblast to myofibroblast differentiation signaling cascades, which regulate the expression of pro-fibrotic proteins and may provide new insights for preterm labor. Full article

Iron overload contributes to proliferative vascular diseases, yet its interplay with hydrogen sulfide (H₂S) in vascular smooth muscle cell (VSMC) proliferation remains poorly understood. This study elucidates H₂S’s role in mitigating iron-overload-induced oxidative stress and cellular damage. Using aortic VSMCs from wildtype (WT) and cystathionine γ-lyase-knockout (CSE-KO) mice treated with ferric ammonium citrate (FAC) at concentrations equivalent to serum levels of iron and citrate, we demonstrate that FAC triggers the integrated stress response (ISR) in WT cells, upregulating CSE to enhance H₂S production. The ISR mediator ATF4 activates caspases but simultaneously induces CSE, which inhibits caspase activity and promotes autophagy via AMPK signaling. In CSE-KO cells, iron overload leads to diminished Ferritin upregulation, unchecked Caspase activation, and impaired autophagy compared to WT cells. Exogenous H₂S restored iron homeostasis by enhancing Ferritin expression, activating NRF2 antioxidant pathways, and restoring apoptosis–autophagy equilibrium in both WT and KO cells. These findings establish H₂S as a critical regulator of iron-induced VSMC dysfunction, highlighting its therapeutic potential in managing vascular pathologies linked to iron dysregulation. Full article

Skeletal muscle satellite cells (SMSCs) are quiescent stem cells located in skeletal muscle tissue and function as the primary reservoir of myogenic progenitors for muscle growth and regeneration. However, the molecular and metabolic mechanisms governing their differentiation in geese remain largely unexplored. This study comprehensively examined the morphological, transcriptional, and metabolic dynamics of goose SMSCs across three critical differentiation stages: the quiescent stage (DD0), the differentiation stage (DD4), and the late differentiation stage (DD6). By integrating transcriptomic and metabolomic analyses, stage-specific molecular signatures and regulatory networks involved in SMSC differentiation were identified. Principal component analysis revealed distinct clustering patterns in gene expression and metabolite profiles across these stages, highlighting dynamic shifts in lipid metabolism and myogenesis. The PPAR signaling pathway emerged as a key regulator, with crucial genes such as PPARG, IGF1, ACSL5, FABP5, and PLIN1 exhibiting differentiation-dependent expression patterns. Notably, PPARG and IGF1 displayed negative correlations with adenosine and L-carnitine levels, suggesting their role in metabolic reprogramming during myotube formation. Additionally, MYOM2 and MYBPC1 exhibited stage-specific regulation and positively correlated with 2,3-dimethoxyphenylamine. This study provides a foundational framework for understanding muscle development and regeneration, offering valuable insights for both agricultural and biomedical research. Full article

Cardiac fibroblasts (CFs) are the essential cell type for heart morphogenesis and homeostasis. In addition to maintaining the structural integrity of the heart tissue, muscle fibroblasts are involved in complex signaling cascades that regulate cardiomyocyte proliferation, migration, and maturation. While CFs serve as the primary source of extracellular matrix proteins (ECM), tissue repair, and paracrine signaling, they are also responsible for adverse pathological changes associated with cardiovascular disease. Following activation, fibroblasts produce excessive ECM components that ultimately lead to fibrosis and cardiac dysfunction. Decades of research have led to a much deeper understanding of the role of CFs in cardiogenesis. Recent studies using the single-cell genomic approach have focused on advancing the role of CFs in cellular interactions, and the mechanistic implications involved during cardiovascular development and disease. Arguably, the unique role of fibroblasts in development, tissue repair, and disease progression categorizes them into the friend or foe category. This brief review summarizes the current understanding of cardiac fibroblast biology and discusses the key findings in the context of development and pathophysiological conditions. Full article

Nanomotors driven by endogenous enzymes are favored in biology and pharmacy due to their spontaneous driving and efficient biocatalytic activity, and have potential applications in the treatment of clinical diseases that are highly dependent on targeted effects. For diseases such as muscle atrophy, using energy molecules such as ATP to improve cellular metabolism is a relatively efficient treatment method. However, traditional adenosine triphosphate (ATP) therapies for muscle atrophy face limitations due to instability under physiological conditions and poor targeting efficiency. To address these challenges, we developed an endogenous proton-gradient-driven ATP transport motor (ATM), a nanomotor integrating chloroplast-derived F_oF₁-ATPase with a biocompatible flask-shaped organic shell (FOS). The ATM is synthesized by vacuum-injecting phospholipid-embedded F_oF₁-ATPase nanothylakoids into ribose-based FOS, enabling autonomous propulsion in acidic microenvironments through proton-driven negative chemotaxis (directional movement away from regions of higher proton concentration). This nanomotor converts proton gradients into ATP synthesis, directly replenishing cellular energy deficits in atrophic tissues. In vitro studies demonstrated high biocompatibility (>90% cell viability at 150 μg/mL) and pH-responsive motility, achieving speeds up to 4.32 μm/s under physiological gradients (ΔpH = 3). In vivo experiments using dexamethasone-induced muscle atrophy mice revealed that ATM treatment accelerated weight recovery and restored normal muscle morphology, with treated mice exhibiting cell sizes comparable to healthy controls (30–40 μm vs. 15–25 μm in untreated). These results highlight the ATM’s potential as a precision therapeutic platform for metabolic disorders, leveraging the natural enzyme functionality and synthetic material design to enhance efficacy while minimizing systemic toxicity. Full article

Both cardiac and skeletal muscles originate from the mesoderm, although the two tissues develop from distinct primordia within the early embryo. The shared, albeit distinctive muscle phenotype of these two cell types have led many researchers to investigate whether stem cells from adult skeletal muscle have the capacity to generate cells with a contractile, cardiac phenotype. To date, most of those studies have relied on multistep protocols requiring tissue engineering, co-cultures or transplantation experimentation. In this report, we describe a simple, cell culture method for obtaining contractile, cardiogenic aggregates from skeletal muscle-derived stem cells (MDSCs). Combining in vitro conditions used for promoting the differentiation of cardiac progenitor cells and the long-term maintenance of heart tissue fragments, we have been able to convert MDSCs to myocardial cells that aggregate into beating myospheres. These selective and optimized culture conditions continued to support a contractile cardiogenic phenotype for over four months in vitro. This culture protocol provides a model for future insights into the pathways responsible for the divergence of skeletal and cardiac phenotypes, as well as a source of easily obtained myocardial tissue for subsequent scientific investigations into cardiac function and biology. Full article

Metamorphosis is a key process in the life history of sea urchin Heliocidaris crassispina. However, the understanding of its molecular mechanisms is still lacking, especially the basic cell biology pre-metamorphosis and post-metamorphosis. Therefore, we employed single-cell RNA sequencing to delineate the cellular states of larvae and juveniles of H. crassispina. Our investigation revealed that the cell composition in sea urchins comprises six primary populations, encompassing nerve cells, skeletogenic cells, immune cells, digestive cells, germ cells, and muscle cells. Subsequently, we identified subpopulations within these cells. Our findings indicated that the larval peripheral nerves were discarded during metamorphosis. A decrease in the number of spicules was observed during this process. Additionally, we examined the differences between larval and adult pigment cells. Meanwhile, cellulase is highlighted as an essential factor for the development of competent juveniles. In summary, this study not only serves as a valuable resource for future research on sea urchins but also deepens our understanding of the intricate metamorphosis process. Full article

The prevalence of cardiovascular disease varies with sex, and the impact of intrinsic sex-based differences on vasculature is not well understood. Animal models can provide important insights into some aspects of human biology; however, not all discoveries in animal systems translate well to humans. To explore the impact of chromosomal sex on proteomic phenotypes, we used iPSC-derived vascular smooth muscle cells from healthy donors of both sexes to identify sex-based proteomic differences and their possible effects on cardiovascular pathophysiology. Our analysis confirmed that differentiated cells have a proteomic profile more similar to healthy primary aortic smooth muscle cells than iPSCs. We also identified sex-based differences in iPSC-derived vascular smooth muscle cells in pathways related to ATP binding, glycogen metabolic process, and cadherin binding as well as multiple proteins relevant to cardiovascular pathophysiology and disease. Additionally, we explored the role of autosomal and sex chromosomes in protein regulation, identifying that proteins on autosomal chromosomes also show sex-based regulation that may affect the protein expression of proteins from autosomal chromosomes. This work supports the biological relevance of iPSC-derived vascular smooth muscle cells as a model for disease, and further exploration of the pathways identified here can lead to the discovery of sex-specific pharmacological targets for cardiovascular disease. Full article

Creatine, a naturally occurring compound in mammals, is crucial in energy metabolism, particularly within muscle and brain tissues. While creatine metabolism in cancer has been studied for several decades, emerging studies are beginning to clarify the sometimes-contradictory role creatine has in either the promotion or inhibition of cancer. On one hand, creatine can directly enhance anti-tumor CD8+ T-cell activity and induce tumor apoptosis, contributing to antitumor immunity. Conversely, other studies have shown that creatine can facilitate cancer cell growth and migration by providing an energy source and activating several signaling pathways. This review will examine what is known about creatine in cancer biology, with a focus on understanding its roles across different cellular compartments. Lastly, we discuss the emerging roles of creatine metabolism, providing exciting new insights into this often-overlooked pathway. This review highlights the complex role of creatine in cancer development and treatment, offering insights into its potential as both a therapeutic target and a risk factor in oncogenesis. Full article