bims-muscge Biomed News
on Muscle stem cells and gene therapy
Issue of 2023–09–17
sixteen papers selected by
Chance Bowman, Dartmouth College
  1. Signaling roles of platelets in skeletal muscle regeneration.
  2. Complex regulatory processes control exercise adaptations of skeletal muscle.
  3. Injury-experienced satellite cells retain long-term enhanced regenerative capacity.
  4. miRNA-126a plays important role in myoblast and endothelial cell interaction.
  5. CRISPR-Cas9 homology-independent targeted integration of exons 1-19 restores full-length dystrophin in mice.
  6. Discordant skeletal muscle gene and protein responses to exercise.
  7. Urgent call to action: Making gene therapy for Duchenne muscular dystrophy (DMD) affordable and accessible.
  8. Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of the skeletal muscle.
  9. Meta-analysis data of skeletal muscle slow fiber content across mammalian species.
  10. Skeletal muscle-directed gene therapy: hijacking the fusogenic properties of muscle cells.
  11. Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers.
  12. Nutrient rescue of early maturing and deteriorating satellite cell-derived engineered muscle tissue.
  13. A split and inducible adenine base editor for precise in vivo base editing.
  14. MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.
  15. Molecular control of endurance training adaptation in male mouse skeletal muscle.
  16. A catch-and-release nano-based gene delivery system.
  1. Bioessays. 2023 Sep 15. e2300134
    Signaling roles of platelets in skeletal muscle regeneration.
    Flavia A Graca, Benjamin A Minden-Birkenmaier, Anna Stephan, Fabio Demontis, Myriam Labelle.
      Platelets have important hemostatic functions in repairing blood vessels upon tissue injury. Cytokines, growth factors, and metabolites stored in platelet α-granules and dense granules are released upon platelet activation and clotting. Emerging evidence indicates that such platelet-derived signaling factors are instrumental in guiding tissue regeneration. Here, we discuss the important roles of platelet-secreted signaling factors in skeletal muscle regeneration. Chemokines secreted by platelets in the early phase after injury are needed to recruit neutrophils to injured muscles, and impeding this early step of muscle regeneration exacerbates inflammation at later stages, compromises neo-angiogenesis and the growth of newly formed myofibers, and reduces post-injury muscle force production. Platelets also contribute to the recruitment of pro-regenerative stromal cells from the adipose tissue, and the platelet releasate may also regulate the metabolism and proliferation of muscle satellite cells, which sustain myogenesis. Therefore, harnessing the signaling functions of platelets and the platelet secretome may provide new avenues for promoting skeletal muscle regeneration in health and disease.
    Keywords:  angiogenesis; muscle repair; neutrophils; platelet secretome; platelet-rich plasma; platelets; skeletal muscle regeneration
    DOI:  https://doi.org/10.1002/bies.202300134
  2. Nat Metab. 2023 Sep 14.
    Complex regulatory processes control exercise adaptations of skeletal muscle.
      
    DOI:  https://doi.org/10.1038/s42255-023-00894-9
  3. Stem Cell Res Ther. 2023 09 12. 14(1): 246
    Injury-experienced satellite cells retain long-term enhanced regenerative capacity.
    Jacopo Morroni, Anna Benedetti, Lorenza Esposito, Marco De Bardi, Giovanna Borsellino, Carles Sanchez Riera, Lorenzo Giordani, Marina Bouche, Biliana Lozanoska-Ochser.
       BACKGROUND: Inflammatory memory or trained immunity is a recently described process in immune and non-immune tissue resident cells, whereby previous exposure to inflammation mediators leads to a faster and stronger responses upon secondary challenge. Whether previous muscle injury is associated with altered responses to subsequent injury by satellite cells (SCs), the muscle stem cells, is not known.
    METHODS: We used a mouse model of repeated muscle injury, in which intramuscular cardiotoxin (CTX) injections were administered 50 days apart in order to allow for full recovery of the injured muscle before the second injury. The effect of prior injury on the phenotype, proliferation and regenerative potential of satellite cells following a second injury was examined in vitro and in vivo by immunohistochemistry, RT-qPCR and histological analysis.
    RESULTS: We show that SCs isolated from muscle at 50 days post-injury (injury-experienced SCs (ieSCs)) enter the cell cycle faster and form bigger myotubes when cultured in vitro, compared to control SCs isolated from uninjured contralateral muscle. Injury-experienced SCs were characterized by the activation of the mTORC 1 signaling pathway, suggesting they are poised to activate sooner following a second injury. Consequently, upon second injury, SCs accumulate in greater numbers in muscle at 3 and 10 days after injury. These changes in SC phenotype and behavior were associated with accelerated muscle regeneration, as evidenced by an earlier appearance of bigger fibers and increased number of myonuclei per fiber at day 10 after the second injury.
    CONCLUSIONS: Overall, we show that skeletal muscle injury has a lasting effect on SC function priming them to respond faster to a subsequent injury. The ieSCs have long-term enhanced regenerative properties that contribute to accelerated regeneration following a secondary challenge.
    Keywords:  Inflammatory memory; Muscle regeneration; Repeated injury; Satellite cells
    DOI:  https://doi.org/10.1186/s13287-023-03492-4
  4. Sci Rep. 2023 Sep 12. 13(1): 15046
    miRNA-126a plays important role in myoblast and endothelial cell interaction.
    Bartosz Mierzejewski, Maria Anna Ciemerych, Wladyslawa Streminska, Katarzyna Janczyk-Ilach, Edyta Brzoska.
      Muscle satellite cells (SCs) are stem cells and the main players in skeletal muscle reconstruction. Since satellite cells are located near or in direct contact with blood vessels their niche is formed, inter alia, by endothelial cells. The cross-talk between satellite cells and endothelial cells determines quiescence or proliferation of these cells. However, little is known about the role of miRNA in these interactions. In the present study we identified miRNA that were up-regulated in SC-derived myoblasts treated with stromal derived factor-1 (SDF-1) and/or down-regulated in cells in which the expression of CXCR4 or CXCR7, that is, SDF-1 receptors, was silenced. SDF-1 is one of the important regulators of cell migration, mobilization, skeletal muscle regeneration, and angiogenesis. We hypothesized that selected miRNAs affect SC-derived myoblast fate and interactions with endothelial cells. We showed that miR-126a-3p inhibited both, myoblast migration and fusion. Moreover, the levels of Cxcl12, encoding SDF-1 and Ackr3, encoding CXCR7, were reduced by miR-126a-3p mimic. Interestingly, the miR-126a-3p mimic significantly decreased the level of numerous factors involved in myogenesis and the miR-126a-5p mimic increased the level of Vefga. Importantly, the treatment of endothelial cells with medium conditioned by miR-126-5p mimic transfected SC-derived myoblasts promoted tubulogenesis.
    DOI:  https://doi.org/10.1038/s41598-023-41626-z
  5. Mol Ther Methods Clin Dev. 2023 Sep 14. 30 486-499
    CRISPR-Cas9 homology-independent targeted integration of exons 1-19 restores full-length dystrophin in mice.
    Anthony A Stephenson, Stefan Nicolau, Tatyana A Vetter, Gabrielle P Dufresne, Emma C Frair, Jessica E Sarff, Gregory L Wheeler, Benjamin J Kelly, Peter White, Kevin M Flanigan.
      Duchenne muscular dystrophy is an X-linked disorder typically caused by out-of-frame mutations in the DMD gene. Most of these are deletions of one or more exons, which can theoretically be corrected through CRISPR-Cas9-mediated knockin. Homology-independent targeted integration is a mechanism for achieving such a knockin without reliance on homology-directed repair pathways, which are inactive in muscle. We designed a system based on insertion into intron 19 of a DNA fragment containing a pre-spliced mega-exon encoding DMD exons 1-19, along with the MHCK7 promoter, and delivered it via a pair of AAV9 vectors in mice carrying a Dmd exon 2 duplication. Maximal efficiency was achieved using a Cas9:donor adeno-associated virus (AAV) ratio of 1:5, with Cas9 under the control of the SPc5-12 promoter. This approach achieved editing of 1.4% of genomes in the heart, leading to 30% correction at the transcript level and restoration of 11% of normal dystrophin levels. Treatment efficacy was lower in skeletal muscles. Sequencing additionally revealed integration of fragmentary and recombined AAV genomes at the target site. These data provide proof of concept for a gene editing system that could restore full-length dystrophin in individuals carrying mutations upstream of intron 19, accounting for approximately 25% of Duchenne muscular dystrophy patients.
    Keywords:  CRISPR-Cas9; Duchenne muscular dystrophy; adeno-associated virus; dystrophin; exon 2 duplication; gene editing; homology-independent targeted integration
    DOI:  https://doi.org/10.1016/j.omtm.2023.08.009
  6. Trends Biochem Sci. 2023 Sep 12. pii: S0968-0004(23)00208-6. [Epub ahead of print]
    Discordant skeletal muscle gene and protein responses to exercise.
    David J Bishop, Nolan J Hoffman, Dale F Taylor, Nicholas J Saner, Matthew J-C Lee, John A Hawley.
      The ability of skeletal muscle to adapt to repeated contractile stimuli is one of the most intriguing aspects of physiology. The molecular bases underpinning these adaptations involve increased protein activity and/or expression, mediated by an array of pre- and post-transcriptional processes, as well as translational and post-translational control. A longstanding dogma assumes a direct relationship between exercise-induced increases in mRNA levels and subsequent changes in the abundance of the proteins they encode. Drawing on the results of recent studies, we dissect and question the common assumption of a direct relationship between changes in the skeletal muscle transcriptome and proteome induced by repeated muscle contractions (e.g., exercise).
    Keywords:  exercise training; mRNA; physical activity; skeletal muscle; transcription
    DOI:  https://doi.org/10.1016/j.tibs.2023.08.005
  7. Br J Clin Pharmacol. 2023 Sep 11.
    Urgent call to action: Making gene therapy for Duchenne muscular dystrophy (DMD) affordable and accessible.
    Omar Alomari.
      
    DOI:  https://doi.org/10.1111/bcp.15900
  8. Skelet Muscle. 2023 Sep 13. 13(1): 15
    Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of the skeletal muscle.
    Stephanie N Oprescu, Nick Baumann, Xiyue Chen, Qiang Sun, Yu Zhao, Feng Yue, Huating Wang, Shihuan Kuang.
      Transcription factors (TFs) play key roles in regulating differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associating domains. Unexpectedly, Myod1Cre-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7CreER- or Rosa26CreER- driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remains to be elucidated.
    Keywords:  Aging; Differentiation; SRY-box transcription factor; Satellite cells; Single-cell RNA-sequencing (scRNA-seq); Stem cells
    DOI:  https://doi.org/10.1186/s13395-023-00324-0
  9. Data Brief. 2023 Oct;50 109520
    Meta-analysis data of skeletal muscle slow fiber content across mammalian species.
    Samantha R Queeno, Kirstin N Sterner, Matthew C O'Neill.
      Herein, the dataset generated for Queeno et al. [1] is presented and described. Mammalian skeletal muscle slow (MyHC-I) fiber composition data was collated from 269 eligible studies identified via a systematic literature search and meta-analysis, following a structure similar to PRISMA [2]. Academic search systems were queried with terms relating to mammalian skeletal muscle fiber content and reference lists of selected articles were thoroughly investigated for additional studies. Eligible studies were those that provided skeletal muscle fiber composition data from mammalian species that were not subjected to experimental manipulations. Taxonomic information, sex, age, number of individuals sampled, average body mass (kg), average slow fiber content (%) of each skeletal muscle under investigation and fiber-typing methodology were collated from eligible studies when available. Muscle fiber composition data was collected from more than 200 skeletal muscles across 174 mammalian species, which will be of value to those interested in muscle physiology, interspecific muscle comparisons, and connections between muscle physiology, taxonomy, body mass, ecomorphology and locomotor strategy (among others).
    Keywords:  Fiber typing; Interspecific muscle physiology comparison; Muscle fiber composition; MyHC I; Myosin heavy chain I; Slow-twitch
    DOI:  https://doi.org/10.1016/j.dib.2023.109520
  10. Signal Transduct Target Ther. 2023 Sep 13. 8(1): 340
    Skeletal muscle-directed gene therapy: hijacking the fusogenic properties of muscle cells.
    Hildegard Büning, Michael Morgan, Axel Schambach.
      
    DOI:  https://doi.org/10.1038/s41392-023-01584-4
  11. Front Cell Dev Biol. 2023 ;11 1209542
    Detyrosinated microtubule arrays drive myofibrillar malformations in mdx muscle fibers.
    Anicca D Harriot, Tessa Altair Morris, Camilo Vanegas, Jacob Kallenbach, Kaylie Pinto, Humberto C Joca, Marie-Jo Moutin, Guoli Shi, Jeanine A Ursitti, Anna Grosberg, Christopher W Ward.
      Altered myofibrillar structure is a consequence of dystrophic pathology that impairs skeletal muscle contractile function and increases susceptibility to contraction injury. In murine Duchenne muscular dystrophy (mdx), myofibrillar alterations are abundant in advanced pathology (>4 months), an age where we formerly established densified microtubule (MT) arrays enriched in detyrosinated (deTyr) tubulin as negative disease modifiers impacting cell mechanics and mechanotransduction. Given the essential role of deTyr-enriched MT arrays in myofibrillar growth, maintenance, and repair, we examined the increased abundance of these arrays as a potential mechanism for these myofibrillar alterations. Here we find an increase in deTyr-tubulin as an early event in dystrophic pathology (4 weeks) with no evidence myofibrillar alterations. At 16 weeks, we show deTyr-enriched MT arrays significantly densified and co-localized to areas of myofibrillar malformation. Profiling the enzyme complexes responsible for deTyr-tubulin, we identify vasohibin 2 (VASH2) and small vasohibin binding protein (SVBP) significantly elevated in the mdx muscle at 4 weeks. Using the genetic increase in VASH2/SVBP expression in 4 weeks wild-type mice we find densified deTyr-enriched MT arrays that co-segregate with myofibrillar malformations similar to those in the 16 weeks mdx. Given that no changes in sarcomere organization were identified in fibers expressing sfGFP as a control, we conclude that disease-dependent densification of deTyr-enriched MT arrays underscores the altered myofibrillar structure in dystrophic skeletal muscle fibers.
    Keywords:  detyrosination; dystrophy; microtubule array; myoarchitecture; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2023.1209542
  12. Tissue Eng Part A. 2023 Sep 11.
    Nutrient rescue of early maturing and deteriorating satellite cell-derived engineered muscle tissue.
    Hironobu Takahashi, Kaho Ishiyama, Naoya Takeda, Tatsuya Shimizu.
      Engineered human muscle tissue is a promising tool for tissue models to better understand muscle physiology and diseases, since they can replicate many biomimetic structures and functions of skeletal muscle in vitro. We have developed a method to produce contractile muscle sheet tissues from human myoblasts, based on our cell sheet fabrication technique. This study reports that our tissue engineering technique allowed us to discover unique characteristics of human muscle satellite cells as a cell source for our muscle sheet tissue. The tissues engineered from satellite cells functionally matured within several days, which is earlier than those created from myoblasts. On the other hand, satellite cell-derived muscle sheet tissues were unable to maintain the contractile ability, whereas the myoblast-derived tissues showed muscle contractions for several weeks. The sarcomere structures and membrane-like structures of laminin and dystrophin were lost along with early functional deterioration. Based on a hypothesis that an insufficiency of nutrients caused a shortened lifetime, we supplemented the culture medium for the satellite cell-derived muscle sheet tissues with 10% serum; although a lower serum medium is commonly used to produce muscle tissues. Further combined with the TGF-1 receptor inhibitor, SB431542, the contractile ability of the muscle tissues was increased remarkably and the tissue microstructures were maintained for a longer term while retaining the early functionalization and the enriched culture conditions prevented early deterioration. These results strengthened our understanding of the biology of myoblasts and satellite cells in muscle tissue formation and provided new insights into the applications of muscle tissue engineering.
    DOI:  https://doi.org/10.1089/ten.TEA.2023.0007
  13. Nat Commun. 2023 Sep 11. 14(1): 5573
    A split and inducible adenine base editor for precise in vivo base editing.
    Hongzhi Zeng, Qichen Yuan, Fei Peng, Dacheng Ma, Ananya Lingineni, Kelly Chee, Peretz Gilberd, Emmanuel C Osikpa, Zheng Sun, Xue Gao.
      DNA base editors use deaminases fused to a programmable DNA-binding protein for targeted nucleotide conversion. However, the most widely used TadA deaminases lack post-translational control in living cells. Here, we present a split adenine base editor (sABE) that utilizes chemically induced dimerization (CID) to control the catalytic activity of the deoxyadenosine deaminase TadA-8e. sABE shows high on-target editing activity comparable to the original ABE with TadA-8e (ABE8e) upon rapamycin induction while maintaining low background activity without induction. Importantly, sABE exhibits a narrower activity window on DNA and higher precision than ABE8e, with an improved single-to-double ratio of adenine editing and reduced genomic and transcriptomic off-target effects. sABE can achieve gene knockout through multiplex splice donor disruption in human cells. Furthermore, when delivered via dual adeno-associated virus vectors, sABE can efficiently convert a single A•T base pair to a G•C base pair on the PCSK9 gene in mouse liver, demonstrating in vivo CID-controlled DNA base editing. Thus, sABE enables precise control of base editing, which will have broad implications for basic research and in vivo therapeutic applications.
    DOI:  https://doi.org/10.1038/s41467-023-41331-5
  14. Cell Rep. 2023 Sep 12. pii: S2211-1247(23)01132-4. [Epub ahead of print]42(9): 113120
    MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.
    Valeria Runfola, Roberto Giambruno, Claudia Caronni, Maria Pannese, Annapaola Andolfo, Davide Gabellini.
      Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays overlapping manifestations with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). FSHD is caused by aberrant gain of expression of the transcription factor double homeobox 4 (DUX4), which triggers a pro-apoptotic transcriptional program resulting in inhibition of myogenic differentiation and muscle wasting. Regulation of DUX4 activity is poorly known. We identify Matrin 3 (MATR3), whose mutation causes ALS and dominant distal myopathy, as a cellular factor controlling DUX4 expression and activity. MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression, rescuing cell viability and myogenic differentiation of FSHD muscle cells, without affecting healthy muscle cells. Finally, we characterize a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent as the full-length protein. Collectively, our data suggest MATR3 as a candidate for developing a treatment for FSHD.
    Keywords:  ALS; CP: Developmental biology; DUX4; FSHD; cell toxicity; gene regulation; muscle differentiation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113120
  15. Nat Metab. 2023 Sep 11.
    Molecular control of endurance training adaptation in male mouse skeletal muscle.
    Regula Furrer, Barbara Heim, Svenia Schmid, Sedat Dilbaz, Volkan Adak, Karl J V Nordström, Danilo Ritz, Stefan A Steurer, Jörn Walter, Christoph Handschin.
      Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. Although morphological changes in endurance-trained muscles are well described, the molecular underpinnings of training adaptation are poorly understood. We therefore aimed to elucidate the molecular signature of muscles of trained male mice and unravel the training status-dependent responses to an acute bout of exercise. Our results reveal that, even though at baseline an unexpectedly low number of genes define the trained muscle, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part associated with epigenetic modifications. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor-γ coactivator 1α are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that underpins muscle plasticity in training.
    DOI:  https://doi.org/10.1038/s42255-023-00891-y
  16. Nanoscale Horiz. 2023 Sep 11.
    A catch-and-release nano-based gene delivery system.
    Christoph O Franck, Andrea Bistrovic Popov, Ishtiaq Ahmed, Rachel E Hewitt, Luise Franslau, Puneet Tyagi, Ljiljana Fruk.
      The design of nanomaterial-based nucleic acid formulations is one of the biggest endeavours in the search for clinically applicable gene delivery systems. Biopolymers represent a promising subclass of gene carriers due to their physicochemical properties, biodegradability and biocompatibility. By modifying melanin-like polydopamine nanoparticles with poly-L-arginine and poly-L-histidine blends, we obtained a novel catch-and-release gene delivery system for efficient trafficking of pDNA to human cells. A synergistic interplay of nanoparticle-bound poly-L-arginine and poly-L-histidine was observed and evaluated for pDNA binding affinity, cell viability, gene release and transfection. Although the functionalisation with poly-L-arginine was crucial for pDNA binding, the resulting nanocarriers failed to release pDNA intracellularly, resulting in limited protein expression. However, optimal pDNA release was achieved through the co-formulation with poly-L-histidine, essential for pDNA release. This effect enabled the design of gene delivery systems, which were comparable to Lipofectamine in terms of transfection efficacy and the catch-and-release surface modification strategy can be translated to other nanocarriers and surfaces.
    DOI:  https://doi.org/10.1039/d3nh00269a
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