DNA Methylation in Skeletal Muscle Stem Cell Specification, Proliferation, and Differentiation

An unresolved and critically important question in skeletal muscle biology is how muscle stem cells initiate and regulate the genetic program during muscle development. Epigenetic dynamics are essential for cellular development and organogenesis in early life and it is becoming increasingly clear that epigenetic remodeling may also be responsible for the cellular adaptations that occur in later life. DNA methylation of cytosine bases within CpG dinucleotide pairs is an important epigenetic modification that reduces gene expression when located within a promoter or enhancer region. Recent advances in the field suggest that epigenetic regulation is essential for skeletal muscle stem cell identity and subsequent cell development. This review summarizes what is currently known about how skeletal muscle stem cells regulate the myogenic program through DNA methylation, discusses a novel role for metabolism in this process, and addresses DNA methylation dynamics in adult skeletal muscle in response to physical activity.

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Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration

eLife ◽

10.7554/elife.26464 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 47

Author(s):

Wenxuan Liu ◽

Alanna Klose ◽

Sophie Forman ◽

Nicole D Paris ◽

Lan Wei-LaPierre ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

Neuromuscular Junction ◽

Neuromuscular Junctions ◽

Aged Mouse ◽

Muscle Stem Cell ◽

Adult Skeletal Muscle ◽

Muscle Stem Cells ◽

Age Related

Neuromuscular junction degeneration is a prominent aspect of sarcopenia, the age-associated loss of skeletal muscle integrity. Previously, we showed that muscle stem cells activate and contribute to mouse neuromuscular junction regeneration in response to denervation (Liu et al., 2015). Here, we examined gene expression profiles and neuromuscular junction integrity in aged mouse muscles, and unexpectedly found limited denervation despite a high level of degenerated neuromuscular junctions. Instead, degenerated neuromuscular junctions were associated with reduced contribution from muscle stem cells. Indeed, muscle stem cell depletion was sufficient to induce neuromuscular junction degeneration at a younger age. Conversely, prevention of muscle stem cell and derived myonuclei loss was associated with attenuation of age-related neuromuscular junction degeneration, muscle atrophy, and the promotion of aged muscle force generation. Our observations demonstrate that deficiencies in muscle stem cell fate and post-synaptic myogenesis provide a cellular basis for age-related neuromuscular junction degeneration and associated skeletal muscle decline.

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The transcription factor NF-Y participates to stem cell fate decision and regeneration in adult skeletal muscle

Nature Communications ◽

10.1038/s41467-021-26293-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Giovanna Rigillo ◽

Valentina Basile ◽

Silvia Belluti ◽

Mirko Ronzio ◽

Elisabetta Sauta ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Transcription Factor ◽

Stem Cell ◽

Satellite Cells ◽

Cell Biology ◽

Myogenic Differentiation ◽

Stem Cell Population ◽

Adult Skeletal Muscle ◽

Muscle Stem Cells

AbstractThe transcription factor NF-Y promotes cell proliferation and its activity often declines during differentiation through the regulation of NF-YA, the DNA binding subunit of the complex. In stem cell compartments, the shorter NF-YA splice variant is abundantly expressed and sustains their expansion. Here, we report that satellite cells, the stem cell population of adult skeletal muscle necessary for its growth and regeneration, express uniquely the longer NF-YA isoform, majorly associated with cell differentiation. Through the generation of a conditional knock out mouse model that selectively deletes the NF-YA gene in satellite cells, we demonstrate that NF-YA expression is fundamental to preserve the pool of muscle stem cells and ensures robust regenerative response to muscle injury. In vivo and ex vivo, satellite cells that survive to NF-YA loss exit the quiescence and are rapidly committed to early differentiation, despite delayed in the progression towards later states. In vitro results demonstrate that NF-YA-depleted muscle stem cells accumulate DNA damage and cannot properly differentiate. These data highlight a new scenario in stem cell biology for NF-Y activity, which is required for efficient myogenic differentiation.

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Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Cells ◽

10.3390/cells8020183 ◽

2019 ◽

Vol 8 (2) ◽

pp. 183 ◽

Cited By ~ 14

Author(s):

David Lee ◽

Akshay Bareja ◽

David Bartlett ◽

James White

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

Muscle Regeneration ◽

Immune Cell ◽

Regenerative Capacity ◽

Adult Skeletal Muscle ◽

Muscle Stem Cells ◽

Age Related ◽

Skeletal Muscle Stem Cells

Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function. Muscle stem cell senescence is associated with a suppression of autophagy during key phases of the regenerative program. Macrophages, a key immune cell involved in muscle repair, also rely on autophagy to aid in tissue repair. This review will focus on the role of autophagy in various aspects of the regenerative program, including adult skeletal muscle stem cells, monocytes/macrophages, and corresponding age-associated dysfunction. Furthermore, we will highlight rejuvenation strategies that alter autophagy to improve muscle regenerative function.

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Progressive and Coordinated Mobilization of the Skeletal Muscle Niche throughout Tissue Repair Revealed by Single-Cell Proteomic Analysis

Cells ◽

10.3390/cells10040744 ◽

2021 ◽

Vol 10 (4) ◽

pp. 744

Author(s):

Matthew Borok ◽

Nathalie Didier ◽

Francesca Gattazzo ◽

Teoman Ozturk ◽

Aurelien Corneau ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

Muscle Regeneration ◽

Cell Types ◽

Skeletal Muscle Regeneration ◽

Muscle Repair ◽

Muscle Stem Cell ◽

Muscle Stem Cells ◽

Cell Lineages

Background: Skeletal muscle is one of the only mammalian tissues capable of rapid and efficient regeneration after trauma or in pathological conditions. Skeletal muscle regeneration is driven by the muscle satellite cells, the stem cell population in interaction with their niche. Upon injury, muscle fibers undergo necrosis and muscle stem cells activate, proliferate and fuse to form new myofibers. In addition to myogenic cell populations, interaction with other cell types such as inflammatory cells, mesenchymal (fibroadipogenic progenitors—FAPs, pericytes) and vascular (endothelial) lineages are important for efficient muscle repair. While the role of the distinct populations involved in skeletal muscle regeneration is well characterized, the quantitative changes in the muscle stem cell and niche during the regeneration process remain poorly characterized. Methods: We have used mass cytometry to follow the main muscle cell types (muscle stem cells, vascular, mesenchymal and immune cell lineages) during early activation and over the course of muscle regeneration at D0, D2, D5 and D7 compared with uninjured muscles. Results: Early activation induces a number of rapid changes in the proteome of multiple cell types. Following the induction of damage, we observe a drastic loss of myogenic, vascular and mesenchymal cell lineages while immune cells invade the damaged tissue to clear debris and promote muscle repair. Immune cells constitute up to 80% of the mononuclear cells 5 days post-injury. We show that muscle stem cells are quickly activated in order to form new myofibers and reconstitute the quiescent muscle stem cell pool. In addition, our study provides a quantitative analysis of the various myogenic populations during muscle repair. Conclusions: We have developed a mass cytometry panel to investigate the dynamic nature of muscle regeneration at a single-cell level. Using our panel, we have identified early changes in the proteome of stressed satellite and niche cells. We have also quantified changes in the major cell types of skeletal muscle during regeneration and analyzed myogenic transcription factor expression in satellite cells throughout this process. Our results highlight the progressive dynamic shifts in cell populations and the distinct states of muscle stem cells adopted during skeletal muscle regeneration. Our findings give a deeper understanding of the cellular and molecular aspects of muscle regeneration.

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Expression and Functional Analyses of Dlk1 in Muscle Stem Cells and Mesenchymal Progenitors during Muscle Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms20133269 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3269 ◽

Cited By ~ 2

Author(s):

Lidan Zhang ◽

Akiyoshi Uezumi ◽

Takayuki Kaji ◽

Kazutake Tsujikawa ◽

Ditte Caroline Andersen ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Muscle Mass ◽

Muscle Regeneration ◽

Muscle Development ◽

Adult Skeletal Muscle ◽

Fat Accumulation ◽

Muscle Stem Cells ◽

Mesenchymal Progenitors ◽

Regeneration Processes

Delta like non-canonical Notch ligand 1 (Dlk1) is a paternally expressed gene which is also known as preadipocyte factor 1 (Pref−1). The accumulation of adipocytes and expression of Dlk1 in regenerating muscle suggests a correlation between fat accumulation and Dlk1 expression in the muscle. Additionally, mice overexpressing Dlk1 show increased muscle weight, while Dlk1-null mice exhibit decreased body weight and muscle mass, indicating that Dlk1 is a critical factor in regulating skeletal muscle mass during development. The muscle regeneration process shares some features with muscle development. However, the role of Dlk1 in regeneration processes remains controversial. Here, we show that mesenchymal progenitors also known as adipocyte progenitors exclusively express Dlk1 during muscle regeneration. Eliminating developmental effects, we used conditional depletion models to examine the specific roles of Dlk1 in muscle stem cells or mesenchymal progenitors. Unexpectedly, deletion of Dlk1 in neither the muscle stem cells nor the mesenchymal progenitors affected the regenerative ability of skeletal muscle. In addition, fat accumulation was not increased by the loss of Dlk1. Collectively, Dlk1 plays essential roles in muscle development, but does not greatly impact regeneration processes and adipogenic differentiation in adult skeletal muscle regeneration.

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Myf6/MRF4 is a Myogenic Niche Regulator Required for the Maintenance of the Muscle Stem Cell Pool

10.1101/691386 ◽

2019 ◽

Author(s):

Felicia Lazure ◽

Darren M. Blackburn ◽

Nabila Karam ◽

Korin Sahinyan ◽

Ahmad Sharanek ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Stem Cell ◽

P38 Map Kinase ◽

Postnatal Life ◽

Muscle Stem Cell ◽

Muscle Stem Cells ◽

Cell Pool ◽

Knockout Animals ◽

Stem Cell Pool

AbstractIn metazoans, skeletal muscle evolved to contract and produce force. However, recent experimental evidence suggests that skeletal muscle has also acquired endocrine functions and produces a vast array of myokines. Using ChIP-Seq and gene expression analyses of myogenic factors, we show that Myf6/MRF4 transcriptionally regulates a broad spectrum of myokines and muscle-secreted proteins, including ligands for downstream activation of key signaling pathways such as EGFR, STAT3 and VEGFR. Homozygous deletion of Myf6 causes a significant reduction in the ability of muscle to produce key myokines such as EGF, VEGFA and LIF. Consequently, although Myf6 knockout mice are born with a normal muscle stem cell compartment, they undergo progressive reduction in their stem cell pool during postnatal life. Mechanistically, muscle stem cells from the Myf6 knockout animals show defects in activation of EGFR and STAT3 signaling, upregulate the p38 MAP kinase pathway and spontaneously break from quiescence. Exogenous application of recombinant EGF and LIF rescue the defects in the muscle stem cell pool of Myf6 knockout animals. Finally, skeletal muscles of mice lacking Myf6 have a significantly reduced ability to sustain donor-engrafted muscle stem cells. Taken together, our data uncovers a novel role for Myf6 in regulating the expression of niche factors and myokines to maintain the skeletal muscle stem cell pool in adult mice.

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