bims-muscge Biomed News
on Muscle stem cells and gene therapy
Issue of 2023–11–19
twenty papers selected by
Chance Bowman, Dartmouth College
  1. The multifaceted role of macrophages in homeostatic and injured skeletal muscle.
  2. [The unexpected role of lipid droplets in the regulation of muscle stem cells fate].
  3. The emerging role of Piezo1 channels in skeletal muscle physiology.
  4. 'Enhancing' skeletal muscle and stem cells in three-dimensional: genome regulation of skeletal muscle in development and disease.
  5. Human skeletal muscle organoids model fetal myogenesis and sustain uncommitted PAX7 myogenic progenitors.
  6. High-mobility group box-1 impedes skeletal muscle regeneration via downregulation of Pax-7 synthesis by increasing miR-342-5p expression.
  7. The L27 Domain of MPP7 enhances TAZ-YY1 Cooperation to Renew Muscle Stem Cells.
  8. [Microtubular network and functionality of the striated skeletal muscle].
  9. [Histone methyltransferases and regenerative myogenesis: A focus on SETDB1].
  10. Cell Therapy Strategies on Duchenne Muscular Dystrophy: A Systematic Review of Clinical Applications.
  11. Effect of Anisotropic Structural Depth on Orientation and Differentiation Behavior of Skeletal Muscle Cells.
  12. PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.
  13. Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy.
  14. Skeletal muscle cells opto-stimulation by intramembrane molecular transducers.
  15. Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease.
  16. Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.
  17. Roles of Skeletal Muscle in Development: A Bioinformatics and Systems Biology Overview.
  18. Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.
  19. The role of RING finger proteins in chromatin remodeling and biological functions.
  20. 3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.
  1. Front Immunol. 2023 ;14 1274816
    The multifaceted role of macrophages in homeostatic and injured skeletal muscle.
    Xingyu Wang, Lan Zhou.
      Skeletal muscle is essential for body physical activity, energy metabolism, and temperature maintenance. It has excellent capabilities to maintain homeostasis and to regenerate after injury, which indispensably relies on muscle stem cells, satellite cells (MuSCs). The quiescence, activation, and differentiation of MuSCs are tightly regulated in homeostatic and regenerating muscles. Among the important regulators are intramuscular macrophages, which are functionally heterogeneous with different subtypes present in a spatiotemporal manner to regulate the balance of different MuSC statuses. During chronic injury and aging, intramuscular macrophages often undergo aberrant activation, which in turn disrupts muscle homeostasis and regenerative repair. Growing evidence suggests that the aberrant activation is mainly triggered by altered muscle microenvironment. The trained immunity that affects myeloid progenitors during hematopoiesis may also contribute. Aged immune system may contribute, in part, to the aging-related sarcopenia and compromised skeletal muscle injury repair. As macrophages are actively involved in the progression of many muscle diseases, manipulating their functional activation has become a promising therapeutic approach, which requires comprehensive knowledge of the cellular and molecular mechanisms underlying the diverse activation. To this end, we discuss here the current knowledge of multifaceted role of macrophages in skeletal muscle homeostasis, injury, and repair.
    Keywords:  aging; homeostasis; injury repair; macrophage; skeletal muscle
    DOI:  https://doi.org/10.3389/fimmu.2023.1274816
  2. Med Sci (Paris). 2023 Nov;39 Hors série n° 1 28-31
    [The unexpected role of lipid droplets in the regulation of muscle stem cells fate].
    Delia Cicciarello, Isabella Scionti.
      Muscle stem cells (MuSCs) are skeletal muscle resident stem cells responsible of skeletal muscle regeneration and tissue integrity maintenance. It is now becoming prominent that the ability of MuSCs either to self-renew or differentiate is affected by cellular metabolism. Recently, a study elucidated that lipid droplets (LDs) are novel key regulators of MuSC fate. Indeed, LDs distribute differently depending on MuSC state during the regeneration process, as LDLow MuSCs are more proned to self-renew while LDHigh MuSCs commit to differentiation. Therefore, these findings highlight that the LD turnover is necessary for MuSC fate decision, opening the question of the molecular mechanism underlying lipid metabolism regulation of MuSC fate determination.
    DOI:  https://doi.org/10.1051/medsci/2023144
  3. Biophys Rev. 2023 Oct;15(5): 1171-1184
    The emerging role of Piezo1 channels in skeletal muscle physiology.
    Timur M Mirzoev.
      Piezo1 channels are mechanically activated (MA) cation channels that are involved in sensing of various mechanical perturbations, such as membrane stretch and shear stress, and play a crucial role in cell mechanotransduction. In response to mechanical stimuli, these channels open up and allow cations to travel into the cell and induce biochemical reactions that can change the cell's metabolism and function. Skeletal muscle cells/fibers inherently depend upon mechanical cues in the form of fluid shear stress and contractions (physical exercise). For example, an exposure of skeletal muscles to chronic mechanical loading leads to increased anabolism and fiber hypertrophy, while prolonged mechanical unloading results in muscle atrophy. MA Piezo1 channels have recently emerged as key mechanosensors that are capable of linking mechanical signals and intramuscular signaling in skeletal muscle cells/fibers. This review will summarize the emerging role of Piezo1 channels in the development and regeneration of skeletal muscle tissue as well as in the regulation of skeletal muscle atrophy. In addition, an overview of potential Piezo1-related signaling pathways underlying anabolic and catabolic processes will be provided. A better understanding of Piezo1's role in skeletal muscle mechanotransduction may represent an important basis for the development of therapeutic strategies for maintaining muscle functions under disuse conditions and in some disease states.
    Keywords:  Intracellular signaling; Mechanotransduction; Myogenesis; Piezo1; Skeletal muscle
    DOI:  https://doi.org/10.1007/s12551-023-01154-6
  4. Curr Opin Genet Dev. 2023 Nov 09. pii: S0959-437X(23)00113-2. [Epub ahead of print]83 102133
    'Enhancing' skeletal muscle and stem cells in three-dimensional: genome regulation of skeletal muscle in development and disease.
    Matthew A Romero, April D Pyle.
      The noncoding genome imparts important regulatory control over gene expression. In particular, gene enhancers represent a critical layer of control that integrates developmental and differentiation signals outside the cell into transcriptional outputs inside the cell. Recently, there has been an explosion in genomic techniques to probe enhancer control, function, and regulation. How enhancers are regulated and integrate signals in stem cell development and differentiation is largely an open question. In this review, we focus on the role gene enhancers play in muscle stem cell specification, differentiation, and progression. We pay specific attention toward the identification of muscle-specific enhancers, the binding of transcription factors to these enhancers, and how enhancers communicate to their target genes via three-dimensional looping.
    DOI:  https://doi.org/10.1016/j.gde.2023.102133
  5. Elife. 2023 Nov 14. pii: RP87081. [Epub ahead of print]12
    Human skeletal muscle organoids model fetal myogenesis and sustain uncommitted PAX7 myogenic progenitors.
    Lampros Mavrommatis, Hyun-Woo Jeong, Urs Kindler, Gemma Gomez-Giro, Marie-Cecile Kienitz, Martin Stehling, Olympia E Psathaki, Dagmar Zeuschner, M Gabriele Bixel, Dong Han, Gabriela Morosan-Puopolo, Daniela Gerovska, Ji Hun Yang, Jeong Beom Kim, Marcos J Arauzo-Bravo, Jens C Schwamborn, Stephan A Hahn, Ralf H Adams, Hans R Schöler, Matthias Vorgerd, Beate Brand-Saberi, Holm Zaehres.
      In vitro culture systems that structurally model human myogenesis and promote PAX7+ myogenic progenitor maturation have not been established. Here we report that human skeletal muscle organoids can be differentiated from induced pluripotent stem cell lines to contain paraxial mesoderm and neuromesodermal progenitors and develop into organized structures reassembling neural plate border and dermomyotome. Culture conditions instigate neural lineage arrest and promote fetal hypaxial myogenesis toward limb axial anatomical identity, with generation of sustainable uncommitted PAX7 myogenic progenitors and fibroadipogenic (PDGFRa+) progenitor populations equivalent to those from the second trimester of human gestation. Single-cell comparison to human fetal and adult myogenic progenitor /satellite cells reveals distinct molecular signatures for non-dividing myogenic progenitors in activated (CD44High/CD98+/MYOD1+) and dormant (PAX7High/FBN1High/SPRY1High) states. Our approach provides a robust 3D in vitro developmental system for investigating muscle tissue morphogenesis and homeostasis.
    Keywords:  Myogenesis; Organoids; Pax7; human; ips cells; regenerative medicine; satellite cells; skeletal muscle; stem cells
    DOI:  https://doi.org/10.7554/eLife.87081
  6. Aging (Albany NY). 2023 Nov 13. 15
    High-mobility group box-1 impedes skeletal muscle regeneration via downregulation of Pax-7 synthesis by increasing miR-342-5p expression.
    Trung-Loc Ho, Yu-Liang Lai, Chin-Jung Hsu, Chen-Ming Su, Chih-Hsin Tang.
      High mobility group box-1 (HMGB1) is a driver of inflammation in various muscular diseases. In a previous study, we determined that HMGB1 induced the atrophy of skeletal muscle by impairing myogenesis. Skeletal muscle regeneration after injury is dependent on pair box 7 (Pax-7)-mediated myogenic differentiation. In the current study, we determined that the HMGB1-induced downregulation of Pax-7 expression in myoblasts inhibited the regeneration of skeletal muscle. We also determined that HMGB1 inhibits Pax-7 and muscle differentiation by increasing miR-342-5p synthesis via receptors for advanced glycation end-products (RAGE), toll-like receptor (TLR) 2, TLR4, and c-Src signaling pathways. In a mouse model involving glycerol-induced muscle injury, the therapeutic inhibition of HMGB1 was shown to rescue Pax-7 expression and muscle regeneration. The HMGB1/Pax-7 axis is a promising therapeutic target to promote muscular regeneration.
    Keywords:  HMGB1; Pax-7; miR-342-5p; muscle regeneration; myoblasts
    DOI:  https://doi.org/10.18632/aging.205202
  7. bioRxiv. 2023 Nov 04. pii: 2023.11.01.565166. [Epub ahead of print]
    The L27 Domain of MPP7 enhances TAZ-YY1 Cooperation to Renew Muscle Stem Cells.
    Anwen Shao, Joseph L Kissil, Chen-Ming Fan.
      Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renewal, for the regenerative process to last a lifetime. How stem cells renew is of critical biological and medical significance. Here we use the skeletal muscle stem cell (MuSC) to study this process. Using a combination of genetic, molecular, and biochemical approaches, we show that MPP7, AMOT, and TAZ/YAP form a complex that activates a common set of target genes. Among these targets, Carm1 can direct MuSC renewal. In the absence of MPP7, TAZ can support regenerative progenitors and activate Carm1 expression, but not to a level needed for self-renewal. Facilitated by the actin polymerization-responsive AMOT, TAZ recruits the L27 domain of MPP7 to up-regulate Carm1 to the level necessary to drive MuSC renewal. The promoter of Carm1 , and those of other common downstream genes, also contain binding site(s) for YY1. We further demonstrate that the L27 domain of MPP7 enhances the interaction between TAZ and YY1 to activate Carm1 . Our results define a renewal transcriptional program embedded within the progenitor program, by selectively up-regulating key gene(s) within the latter, through the combination of protein interactions and in a manner dependent on the promoter context.
    DOI:  https://doi.org/10.1101/2023.11.01.565166
  8. Med Sci (Paris). 2023 Nov;39 Hors série n° 1 54-57
    [Microtubular network and functionality of the striated skeletal muscle].
    Léa Castellano, Vincent Gache.
      Striated skeletal muscles are made of post-mitotic and multinucleated cells: muscle fibers, in which nuclei are regularly spaced and positioned at their periphery. The specific positioning of nuclei, necessary for the proper functioning of the muscle, is mainly regulated by the microtubule network and partner proteins. Many muscular pathologies present alterations in both the organization of the microtubule network and nuclear positioning, as observed in Duchenne Muscular Dystrophy, centronuclear myopathies or various neuromuscular diseases. The importance of the microtubule interactome and its influence in the maintenance of skeletal muscle homeostasis is a key issue in understanding muscle diseases.
    DOI:  https://doi.org/10.1051/medsci/2023146
  9. Med Sci (Paris). 2023 Nov;39 Hors série n° 1 11-14
    [Histone methyltransferases and regenerative myogenesis: A focus on SETDB1].
    Pauline Garcia, Fabien Le Grand.
      Adult skeletal muscle is composed of thousands of fibers (also called myofibers) that contract thus allowing voluntary movements. Following an injury, muscle stem cells, surrounding the myofibers, activate, proliferate, and differentiate to form de novo myofibers. These steps constitute a process called adult (or regenerative) myogenesis. This process is possible thanks to various transcription factors sequentially expressed and regulated by epigenetic factors that modulate the chromatin and therefore lead to the regulation of gene expression. Gene expression changes consequently affect the fate of muscle stem cells. Histone Lysine Methyltransferases methylate some histones involved in the repression of gene expression. We describe here the role of SETDB1 during adult myogenesis, notably its role during muscle stem cell differentiation.
    DOI:  https://doi.org/10.1051/medsci/2023145
  10. Stem Cell Rev Rep. 2023 Nov 13.
    Cell Therapy Strategies on Duchenne Muscular Dystrophy: A Systematic Review of Clinical Applications.
    Ayberk Akat, Erdal Karaöz.
      Duchenne Muscular Dystrophy (DMD) is an inherited genetic disorder characterized by progressive degeneration of muscle tissue, leading to functional disability and premature death. Despite extensive research efforts, the discovery of a cure for DMD continues to be elusive, emphasizing the need to investigate novel treatment approaches. Cellular therapies have emerged as prospective approaches to address the underlying pathophysiology of DMD. This review provides an examination of the present situation regarding cell-based therapies, including CD133 + cells, muscle precursor cells, mesoangioblasts, bone marrow-derived mononuclear cells, mesenchymal stem cells, cardiosphere-derived cells, and dystrophin-expressing chimeric cells. A total of 12 studies were found eligible to be included as they were completed cell therapy clinical trials, clinical applications, or case reports with quantitative results. The evaluation encompassed an examination of limitations and potential advancements in this particular area of research, along with an assessment of the safety and effectiveness of cell-based therapies in the context of DMD. In general, the available data indicates that diverse cell therapy approaches may present a new, safe, and efficacious treatment modality for patients diagnosed with DMD. However, further studies are required to comprehensively understand the most advantageous treatment approach and therapeutic capacity.
    Keywords:  Cell Therapy; Clinical Trials; Duchenne Muscular Dystrophy; Regenerative Medicine
    DOI:  https://doi.org/10.1007/s12015-023-10653-8
  11. ACS Omega. 2023 Nov 07. 8(44): 41374-41382
    Effect of Anisotropic Structural Depth on Orientation and Differentiation Behavior of Skeletal Muscle Cells.
    Jianfeng Chen, Xuefei Chen, Yihao Ma, Yiran Liu, Jin Li, Kai Peng, Yichuan Dai, Xiaoxiao Chen.
      Extensive research has been conducted to examine how substrate topological factors are involved in modulating the cell behavior. Among numerous topological factors, the vital influence of the touchable depth of substrates on cell behaviors has already been extensively characterized, but the response of cells to the topological structure at untouchable depth is still elusive. Herein, the influences of substrate depth on myoblast behaviors are systematically investigated using substrates with depths ranging from touchable depth (microgrooved) to untouchable depth (microbridges). The results show that an increase in microgroove depth is accompanied by an inhibited cell spreading, an enhanced elongation, and a more obvious orientation along microgrooves. Interestingly, myoblasts located on microbridges show a more pronounced elongation with increasing culture time but a position-dependent orientation. Myoblasts on the center and parallel boundary of microbridges orient along the bridges, while myoblasts on the vertical boundary align perpendicular to the microbridges. Moreover, the differentiation results of the myoblasts indicate that the differentiated myotubes can maintain this position-dependent orientation. The simulation of the stress field in cell monolayers suggests that the position-dependent orientation is caused by the comprehensive response of myoblasts to the substrate discontinuity and substrate depth. These findings provide valuable insights into the mechanism of cell depth sensing and could inform the design of tissue engineering scaffolds for skeletal muscle and biohybrid actuation.
    DOI:  https://doi.org/10.1021/acsomega.3c04981
  12. Nat Commun. 2023 Nov 15. 14(1): 7291
    PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors.
    Madeline B Searcy, Randolph K Larsen, Bradley T Stevens, Yang Zhang, Hongjian Jin, Catherine J Drummond, Casey G Langdon, Katherine E Gadek, Kyna Vuong, Kristin B Reed, Matthew R Garcia, Beisi Xu, Darden W Kimbrough, Grace E Adkins, Nadhir Djekidel, Shaina N Porter, Patrick A Schreiner, Shondra M Pruett-Miller, Brian J Abraham, Jerold E Rehg, Mark E Hatley.
      Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.
    DOI:  https://doi.org/10.1038/s41467-023-43044-1
  13. Biochem J. 2023 Nov 15. 480(21): 1767-1789
    Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy.
    Valeria Di Leo, Tiago M Bernardino Gomes, Amy E Vincent.
      Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.
    Keywords:  function; metabolism; mitochondria; mitochondrial dysfunction; structure
    DOI:  https://doi.org/10.1042/BCJ20220233
  14. Commun Biol. 2023 11 11. 6(1): 1148
    Skeletal muscle cells opto-stimulation by intramembrane molecular transducers.
    Ilaria Venturino, Vito Vurro, Silvio Bonfadini, Matteo Moschetta, Sara Perotto, Valentina Sesti, Luigino Criante, Chiara Bertarelli, Guglielmo Lanzani.
      Optical stimulation and control of muscle cell contraction opens up a number of interesting applications in hybrid robotic and medicine. Here we show that recently designed molecular phototransducer can be used to stimulate C2C12 skeletal muscle cells, properly grown to exhibit collective behaviour. C2C12 is a skeletal muscle cell line that does not require animal sacrifice Furthermore, it is an ideal cell model for evaluating the phototransducer pacing ability due to its negligible spontaneous activity. We study the stimulation process and analyse the distribution of responses in multinuclear cells, in particular looking at the consistency between stimulus and contraction. Contractions are detected by using an imaging software for object recognition. We find a deterministic response to light stimuli, yet with a certain distribution of erratic behaviour that is quantified and correlated to light intensity or stimulation frequency. Finally, we compare our optical stimulation with electrical stimulation showing advantages of the optical approach, like the reduced cell stress.
    DOI:  https://doi.org/10.1038/s42003-023-05538-y
  15. Cell Rep. 2023 Nov 10. pii: S2211-1247(23)01448-1. [Epub ahead of print]42(11): 113436
    Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease.
    Ian Matthews, Allison Birnbaum, Anastasia Gromova, Amy W Huang, Kailin Liu, Eleanor A Liu, Kristen Coutinho, Megan McGraw, Dalton C Patterson, Macy T Banks, Amber C Nobles, Nhat Nguyen, Gennifer E Merrihew, Lu Wang, Eric Baeuerle, Elizabeth Fernandez, Nicolas Musi, Michael J MacCoss, Helen C Miranda, Albert R La Spada, Constanza J Cortes.
      Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.
    Keywords:  CP: Neuroscience; TFEB; aging; brain; exercise; muscle; neurodegeneration; tau
    DOI:  https://doi.org/10.1016/j.celrep.2023.113436
  16. bioRxiv. 2023 Oct 23. pii: 2023.10.19.563160. [Epub ahead of print]
    Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure.
    Anthony L Hessel, Michel Kuehn, Seong-Won Han, Weikang Ma, Thomas C Irving, Brent A Momb, Taejeong Song, Sakthivel Sadayappan, Wolfgang A Linke, Bradley M Palmer.
      In striated muscle, some sarcomere proteins regulate crossbridge cycling by varying the propensity of myosin heads to interact with actin. Myosin-binding protein C (MyBP-C) is bound to the myosin thick filament and is predicted to interact and stabilize myosin heads in a docked position against the thick filament and limit crossbridge formation, the so-called OFF state. Via an unknown mechanism, MyBP-C is thought to release heads into the so-called ON state, where they are more likely to form crossbridges. To study this proposed mechanism, we used the C2 -/- mouse line to knock down fast-isoform MyBP-C completely and total MyBP-C by ∼24%, and conducted mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2 -/- fibers presented deficits in force production and reduced calcium sensitivity. Structurally, passive C2 -/- fibers presented altered SL-independent and SL-dependent regulation of myosin head ON/OFF states, with a shift of myosin heads towards the ON state. Unexpectedly, at shorter sarcomere lengths, the thin filament was axially extended in C2 -/- vs. non-transgenic controls, which we postulate is due to increased low-level crossbridge formation arising from relatively more ON myosins in the passive muscle that elongates the thin filament. The downstream effect of increasing crossbridge formation in a passive muscle on contraction performance is not known. Such widespread structural changes to sarcomere proteins provide testable mechanisms to explain the etiology of debilitating MyBP-C-associated diseases.
    DOI:  https://doi.org/10.1101/2023.10.19.563160
  17. Adv Anat Embryol Cell Biol. 2023 ;236 21-55
    Roles of Skeletal Muscle in Development: A Bioinformatics and Systems Biology Overview.
    Jean-Sebastien Milanese, Richard Marcotte, Willard J Costain, Boris Kablar, Simon Drouin.
      The ability to assess various cellular events consequent to perturbations, such as genetic mutations, disease states and therapies, has been recently revolutionized by technological advances in multiple "omics" fields. The resulting deluge of information has enabled and necessitated the development of tools required to both process and interpret the data. While of tremendous value to basic researchers, the amount and complexity of the data has made it extremely difficult to manually draw inference and identify factors key to the study objectives. The challenges of data reduction and interpretation are being met by the development of increasingly complex tools that integrate disparate knowledge bases and synthesize coherent models based on current biological understanding. This chapter presents an example of how genomics data can be integrated with biological network analyses to gain further insight into the developmental consequences of genetic perturbations. State of the art methods for conducting similar studies are discussed along with modern methods used to analyze and interpret the data.
    Keywords:  Bioinformatics; Genomics; Microarray; Network analysis; Sequencing; Systems biology
    DOI:  https://doi.org/10.1007/978-3-031-38215-4_2
  18. Signal Transduct Target Ther. 2023 Nov 13. 8(1): 427
    Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases.
    Priyanka Dey Talukdar, Urmi Chatterji.
      Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators. Deregulation of these regulatory molecules is associated with cell state transitions, which in turn is accountable for diverse maladies, including developmental disorders, metabolic disorders, and most significantly, cancer. A decade back most transcription factors, the key enablers of disease development, were historically viewed as 'undruggable'; however, in the intervening years, a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators, their confederates in various physiological and molecular processes. These co-activators, along with transcription factors, have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions, whereby, deregulation of such interactions may foster tissue-specific disease phenotype. Hence, it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors. The proposed review attempts to elaborate an in-depth account of the transcription co-activators, their involvement in transcription regulation, and context-specific contributions to pathophysiological conditions. This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly therapeutic strategies, where drugs targeting co-activators will have enhanced benefits and reduced side effects. Additional insights into currently available therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced therapeutic targets aiming for disease amelioration and good patient prognosis.
    DOI:  https://doi.org/10.1038/s41392-023-01651-w
  19. Epigenomics. 2023 Nov 15.
    The role of RING finger proteins in chromatin remodeling and biological functions.
    Xiaoxue Chai, Qian Tao, Lili Li.
      Mammalian DNA duplexes are highly condensed with different components, including histones, enabling chromatin formation. Chromatin remodeling is involved in multiple biological processes, including gene transcription regulation and DNA damage repair. Recent research has highlighted the significant involvement of really interesting new gene (RING) finger proteins in chromatin remodeling, primarily attributed to their E3 ubiquitin ligase activities. In this review, we highlight the pivotal role of RING finger proteins in chromatin remodeling and provide an overview of their capacity to ubiquitinate specific histones, modulate ATP-dependent chromatin remodeling complexes and interact with various histone post-translational modifications. We also discuss the diverse biological effects of RING finger protein-mediated chromatin remodeling and explore potential therapeutic strategies for targeting these proteins.
    Keywords:  DNA damage repair; E3 ubiquitin ligase; RING finger protein; chromatin remodeling; transcriptional regulation
    DOI:  https://doi.org/10.2217/epi-2023-0234
  20. Aging Cell. 2023 Nov 13. e14009
    3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.
    Zer Vue, Edgar Garza-Lopez, Kit Neikirk, Prasanna Katti, Larry Vang, Heather Beasley, Jianqiang Shao, Andrea G Marshall, Amber Crabtree, Alexandria C Murphy, Brenita C Jenkins, Praveena Prasad, Chantell Evans, Brittany Taylor, Margaret Mungai, Mason Killion, Dominique Stephens, Trace A Christensen, Jacob Lam, Benjamin Rodriguez, Mark A Phillips, Nastaran Daneshgar, Ho-Jin Koh, Alice Koh, Jamaine Davis, Nina Devine, Saleem Muhammod, Estevão Scudese, Kenneth Ryan Arnold, Valeria Vanessa Chavarin, Ryan Daniel Robinson, Moumita Chakraborty, Jennifer A Gaddy, Mariya T Sweetwyne, Genesis Wilson, Elma Zaganjor, James Kezos, Cristiana Dondi, Anilkumar K Reddy, Brian Glancy, Annet Kirabo, Anita M Quintana, Dao-Fu Dai, Karen Ocorr, Sandra A Murray, Steven M Damo, Vernat Exil, Blake Riggs, Bret C Mobley, Jose A Gomez, Melanie R McReynolds, Antentor Hinton.
      During aging, muscle gradually undergoes sarcopenia, the loss of function associated with loss of mass, strength, endurance, and oxidative capacity. However, the 3D structural alterations of mitochondria associated with aging in skeletal muscle and cardiac tissues are not well described. Although mitochondrial aging is associated with decreased mitochondrial capacity, the genes responsible for the morphological changes in mitochondria during aging are poorly characterized. We measured changes in mitochondrial morphology in aged murine gastrocnemius, soleus, and cardiac tissues using serial block-face scanning electron microscopy and 3D reconstructions. We also used reverse transcriptase-quantitative PCR, transmission electron microscopy quantification, Seahorse analysis, and metabolomics and lipidomics to measure changes in mitochondrial morphology and function after loss of mitochondria contact site and cristae organizing system (MICOS) complex genes, Chchd3, Chchd6, and Mitofilin. We identified significant changes in mitochondrial size in aged murine gastrocnemius, soleus, and cardiac tissues. We found that both age-related loss of the MICOS complex and knockouts of MICOS genes in mice altered mitochondrial morphology. Given the critical role of mitochondria in maintaining cellular metabolism, we characterized the metabolomes and lipidomes of young and aged mouse tissues, which showed profound alterations consistent with changes in membrane integrity, supporting our observations of age-related changes in muscle tissues. We found a relationship between changes in the MICOS complex and aging. Thus, it is important to understand the mechanisms that underlie the tissue-dependent 3D mitochondrial phenotypic changes that occur in aging and the evolutionary conservation of these mechanisms between Drosophila and mammals.
    Keywords:   Drosophila ; 3D morphometry; MICOS; aging; mitochondria; mitochondrial disease; mitochondrion; reconstruction; reticulum; serial block-face SEM; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.14009
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