Satellite Cell Fate Research Articles

Featured characteristics and pivotal roles of satellite cells in skeletal muscle regeneration

Skeletal muscle, the essential organ for locomotion, as well as energy reservoir and expenditure, has robust regenerative capacity in response to mechanical stress and injury. As muscle-specific stem cells, satellite cells are responsible for providing new myoblasts during the process of muscle growth and regeneration. Self-renewal capacity and the fate of satellite cells are highly regulated and influenced by their surrounding factors, such as extracellular matrix and soluble proteins. The strong myogenic potential of satellite cells makes them a potential resource for stem cell therapy to cure genetic muscle disease and repair injured muscle. Here, we both review key features of satellite cells during skeletal muscle development and regeneration and summarize recent outcomes of satellite cell transplantation studies.

NEUROGENIC HETEROTOPIC OSSIFICATIONS ARE DERIVED FROM FIBROADIPOGENIC PROGENITORS IN THE SKELETAL MUSCLE NOT FROM SATELLITE CELLS

Neurological heterotopic ossifications (NHO) are frequent complications of traumatic brain and spinal cord injuries (SCI). NHO are abnormal ossifications within periarticular muscles resulting in joint ankylosis, vessel and nerve compression. To elucidate NHO pathogenesis, we have developed the first murine model of SCI-NHO, in which NHO is induced in cardiotoxin-injured muscle only following a SCI. However, what stem cell populations within muscle differentiate into osteoblasts and directly contribute to NHO is unclear. We hypothesized that injured muscles do not repair normally after SCI, and instead osteogenic differentiation of skeletal muscle-resident stem cells takes place. We focused on the two progenitor populations known to reside in muscles: satellite cells (SCs) and fibro- adipogenic progenitors (FAPs). SCs, which specifically express the transcription factor Pax7, differentiate into myoblasts, whereas FAPs, which express are of mesenchymal origin and express Prrx1+ instead, can differentiate into fibroblasts and adipocytes in vitro. We had shown that both populations can deposit calcium under osteogenic condition in vitro. We have now generated Pax7CreER x R26-ZsGreen (Pax7ZsG) and Prrx1Cre x R26-ZsGreen (Prrx1ZsG) to specifically trace the fate of SCs and FAPs respectively in our NHO model in vivo. We demonstrate that after SCI, Pax7+ SCs fail to proliferate and regenerate myofibers with instead persistent proliferation of Prrx1+ FAPs differentiating into osteocalcin+ osteoblasts in SCI-NHO at 21 days post-surgery. The above suggest that SCI causes muscle repair failure with instead proliferation and osteogenic differentiation of FAPs residing in the muscle. In addition, SCI significantly upregulated platelet-derived growth factor receptor (PDGFR) expression in FAPs indicating dysregulation of PDGFR signalling may be involved in the NHO development.

Exercise and the control of muscle mass in human.

During the course of life, muscle mass undergoes many changes in terms of quantity and quality. Skeletal muscle is a dynamic tissue able to hypertrophy or atrophy according to growth, ageing, physical activity, nutrition and health state. The purpose of the present review is to present the mechanisms by which exercise can induce changes in human skeletal muscle mass by modulating protein balance and regulating the fate of satellite cells. Exercise is known to exert transcriptional, translational and post-translational regulations as well as to induce epigenetic modifications and to control messenger RNA stability, which all contribute to the regulation of protein synthesis. Exercise also regulates the autophagy-lysosomal and the ubiquitin-proteasome pathways, the two main proteolytic systems in skeletal muscle, indicating that exercise participates to the regulation of the quality control mechanisms of cellular components and, therefore, to muscle health. Finally, activation, proliferation and differentiation of satellite cells can be enhanced by exercise to induce muscle remodelling and hypertrophy. Each of these mechanisms can potentially impact skeletal muscle mass, depending on the intensity, duration and frequency with which the signal appears.

Dietary Butyrate, an HDAC Inhibitor, Primes Muscle Satellite Cells for Differentiation by Altering the Epigenetic Landscape

Satellite cells (SC) are a heterogeneous population of skeletal muscle resident stem cells that are responsible for postnatal muscle growth and repair. Satellite cells lie in a state of quiescence along the muscle fiber where they will activate, proliferate, and either self‐renew or differentiate. With the investigation into the genomic regulation of satellite cell fate, we now have an idea as to how the satellite cell epigenome governs myogenesis. Specifically, changes in the chromatin structure and the regulators that direct these changes modulate SC activation, proliferation, and differentiation. Interestingly, histone deacetylase (HDAC) inhibitors have proven to be effective at enhancing the myogenic program of SC, but their precise mode of action in altering the epigenetic landscape of SC remains undetermined. Our objective was to determine how a HDAC inhibitor, butyrate, promotes myogenic differentiation. Twenty female neonatal piglets (24±8hrs old) were fed a standard milk replacer or one supplemented with 0.50% (on a dry‐matter basis) spray dried Tributyrin (TB), a butyrate pro‐drug, for 17d. Satellite cells from TB supplemented piglets showed a decrease in the expression of EZH2 (enhancer of zeste homolog 2), the methyltransferase subunit of the PRC2 (polycomb repressive complex 2), just prior to being induced to differentiate. ChIP‐Seq analysis revealed that SC from TB treated piglets resulted in a global reduction of the repressive chromatin mark H3K27me3. Of the 532 differentially enriched regions (DER), TB treatment decreased binding at 358 sites, specifically those sites associated with genes involved in myogenic differentiation, negative regulation of cell proliferation, and micro‐RNAs normally upregulated during differentiation. ChIP‐Seq analysis for global enrichment of H3K27ac did not reveal any numerical differences in DER resulting from TB treatment. Given that EZH2 is responsible for the deposition of the repressive H3K27me3 mark, SC were transfected with siRNA targeting the EZH2 transcript (siEZH2), treated with 0.5 mM sodium butyrate (NaBu), or both (siEZH2 + NaBu) to determine if this was the primary mechanism through which butyrate alters SC myogenesis. Treatment with NaBu and siEZH2 reduced EZH2 expression in an additive manner. Treatment with NaBu alone and with siEZH2 significantly reduced Pax7 and MyoD expression after 24h of treatment while siEZH2 treatment had no effect on the expression of these myogenic transcription factors. Immunostaining for the contractile protein myosin heavy chain (MyHC) revealed an increase in MyHC+ cells from the siEZH2 treatment group after 72h of differentiation; however, these cells did not form multinucleated myotubes. The epigenetic changes caused by dietary TB supplementation resulted in reduced EZH2 and EZH2 trimethylation of H3K27. Taken together, these results indicate that while EZH2 ablation may force myogenic differentiation, butyrate may operate through a parallel mechanism to enhance differentiation. These findings help support the notion that butyrate may be used to enhance muscle growth and could prove useful at treating myopathic conditions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells

Satellite cells are muscle stem cells required for muscle regeneration upon damage. Of note, satellite cells are bipotent and have the capacity to differentiate not only into skeletal myocytes, but also into brown adipocytes. Epigenetic mechanisms regulating fate decision and differentiation of satellite cells during muscle regeneration are not yet fully understood. Here, we show that elevated levels of lysine-specific demethylase 1 (Kdm1a, also known as Lsd1) have a beneficial effect on muscle regeneration and recovery after injury, since Lsd1 directly regulates key myogenic transcription factor genes. Importantly, selective Lsd1 ablation or inhibition in Pax7-positive satellite cells, not only delays muscle regeneration, but changes cell fate towards brown adipocytes. Lsd1 prevents brown adipocyte differentiation of satellite cells by repressing expression of the novel pro-adipogenic transcription factor Glis1. Together, downregulation of Glis1 and upregulation of the muscle-specific transcription program ensure physiological muscle regeneration.

Castration induces satellite cell activation that contributes to skeletal muscle maintenance

Sarcopenia, the age-related loss of skeletal muscle, is a side effect of androgen deprivation therapy (ADT) for prostate cancer patients. Resident stem cells of skeletal muscle, satellite cells (SCs), are an essential source of progenitors for the growth and regeneration of skeletal muscle. Decreased androgen signaling and deficits in the number and function of SCs are features of aging. Although androgen signaling is known to regulate skeletal muscle, the cellular basis for ADT-induced exacerbation of sarcopenia is unknown. Furthermore, the consequences of androgen deprivation on SC fate in adult skeletal muscle remain largely unexplored. We examined SC fate in an androgen-deprived environment using immunofluorescence and fluorescence-activated cell sorting (FACS) with SC-specific markers in young castrated mice. To study the effects of androgen deprivation on SC function and skeletal muscle regenerative capacity, young castrated mice were subjected to experimental regenerative paradigms. SC-derived-cell contributions to skeletal muscle maintenance were examined in castrated Pax7CreER/+; ROSA26mTmG/+ mice. SCs were depleted in Pax7CreER/+; ROSA26DTA/+ mice to ascertain the consequences of SC ablation in sham and castrated skeletal muscles. Confocal immunofluorescence analysis of neuromuscular junctions (NMJs), and assessment of skeletal muscle physiology, contractile properties, and integrity were conducted. Castration led to SC activation, however this did not result in a decline in SC function or skeletal muscle regenerative capacity. Surprisingly, castration induced SC-dependent maintenance of young skeletal muscle. The functional dependence of skeletal muscles on SCs in young castrated mice was demonstrated by an increase in SC-derived-cell fusion within skeletal muscle fibers. SC depletion was associated with further atrophy and functional decline, as well as the induction of partial innervation and the loss of NMJ-associated myonuclei in skeletal muscles from castrated mice. The maintenance of skeletal muscles in young castrated mice relies on the cellular contributions of SCs. Considering the well-described age-related decline in SCs, the results in this study highlight the need to devise strategies that promote SC maintenance and activity to attenuate or reverse the progression of sarcopenia in elderly androgen-deprived individuals.

Tethered Jagged-1 Synergizes with Culture Substrate Stiffness to Modulate Notch-Induced Myogenic Progenitor Differentiation.

Notch signaling is amongst the key intrinsic mechanisms regulating satellite cell fate, promoting the transition of activated satellite cells to highly proliferative myogenic progenitor cells and preventing their premature differentiation. Although much is known about the biochemical milieu that drives myogenic progression, less is known about the spatial cues providing spatiotemporal control of skeletal muscle repair in the context of Notch signaling. Using a murine injury model, we quantified in vivo biophysical changes that occur within the skeletal muscle during regeneration. Employing tunable poly(ethylene glycol)-based hydrogel substrates, we modeled the measured changes in bulk stiffness in the context of Notch ligand signaling, which are present in the regenerative milieu at the time of injury. Following injury, there is a transient increase in the bulk stiffness of the tibialis anterior muscle that may be explained in part by changes in extracellular matrix deposition. When presented to primary myoblasts, Jagged-1, Jagged-2, and Dll1 in a tethered format elicited greater degrees of Notch activity compared to their soluble form. Only tethered Jagged-1 effects were tuned by substrate stiffness, with the greatest Notch activation observed on stiff hydrogels matching the stiffness of regenerating muscle. When exposed to tethered Jagged-1 on stiff hydrogels, fewer primary myoblasts expressed myogenin, and pharmacological inhibitor studies suggest this effect is Notch and RhoA dependent. Our study proposes that tethered Jagged-1 presented in the context of transient tissue stiffening serves to tune Notch activity in myogenic progenitors during skeletal muscle repair and delay differentiation.

Pitx2 in Embryonic and Adult Myogenesis.

Skeletal muscle is a heterogeneous tissue that represents between 30 and 38% of the human body mass and has important functions in the organism, such as maintaining posture, locomotor impulse, or pulmonary ventilation. The genesis of skeletal muscle during embryonic development is a process controlled by an elaborate regulatory network combining the interplay of extrinsic and intrinsic regulatory mechanisms that transform myogenic precursor cells into functional muscle fibers through a finely tuned differentiation program. However, the capacity of generating muscle still remains once these fibers have matured. Adult myogenesis resembles many of the embryonic morphogenetic episodes and depends on the activation of satellite cells that have the potential to differentiate into new muscle fibers. Pitx2 is a member of the bicoid family of homeodomain transcription factors that play an important role in morphogenesis. In the last decade, Pitx2 has emerged as a key element involved in the fine-tuning mechanism that regulates skeletal-muscle development as well as the differentiation and cell fate of satellite cells in adult muscle. Here we present an integrative view of all aspects of embryonic and adult myogenesis in which Pitx2 is involved, from embryonic development to satellite-cell proliferation, fate specification, and differentiation. Those new Pitx2 functions on satellite-cell biology might open new perspectives to develop therapeutic strategies for muscular disorders.

Karyopherin Alpha 1 Regulates Satellite Cell Proliferation and Survival by Modulating Nuclear Import.

Satellite cells are stem cells with an essential role in skeletal muscle repair. Precise regulation of gene expression is critical for proper satellite cell quiescence, proliferation, differentiation and self-renewal. Nuclear proteins required for gene expression are dependent on the nucleocytoplasmic transport machinery to access to nucleus, however little is known about regulation of nuclear transport in satellite cells. The best characterized nuclear import pathway is classical nuclear import which depends on a classical nuclear localization signal (cNLS) in a cargo protein and the heterodimeric import receptors, karyopherin alpha (KPNA) and beta (KPNB). Multiple KPNA1 paralogs exist and can differ in importing specific cNLS proteins required for cell differentiation and function. We show that transcripts for six Kpna paralogs underwent distinct changes in mouse satellite cells during muscle regeneration accompanied by changes in cNLS proteins in nuclei. Depletion of KPNA1, the most dramatically altered KPNA, caused satellite cells in uninjured muscle to prematurely activate, proliferate and undergo apoptosis leading to satellite cell exhaustion with age. Increased proliferation of satellite cells led to enhanced muscle regeneration at early stages of regeneration. In addition, we observed impaired nuclear localization of two key KPNA1 cargo proteins: p27, a cyclin-dependent kinase inhibitor associated with cell cycle control and lymphoid enhancer factor 1, a critical cotranscription factor for β-catenin. These results indicate that regulated nuclear import of proteins by KPNA1 is critical for satellite cell proliferation and survival and establish classical nuclear import as a novel regulatory mechanism for controlling satellite cell fate. Stem Cells 2016;34:2784-2797.

Ck2-Dependent Phosphorylation Is Required to Maintain Pax7 Protein Levels in Proliferating Muscle Progenitors

Skeletal muscle regeneration and long term maintenance is directly link to the balance between self-renewal and differentiation of resident adult stem cells known as satellite cells. In turn, satellite cell fate is influenced by a functional interaction between the transcription factor Pax7 and members of the MyoD family of muscle regulatory factors. Thus, changes in the Pax7-to-MyoD protein ratio may act as a molecular rheostat fine-tuning acquisition of lineage identity while preventing precocious terminal differentiation. Pax7 is expressed in quiescent and proliferating satellite cells, while its levels decrease sharply in differentiating progenitors Pax7 is maintained in cells (re)acquiring quiescence. While the mechanisms regulating Pax7 levels based on differentiation status are not well understood, we have recently described that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4, thus promoting proteasome-dependent Pax7 degradation in differentiating satellite cells. Here we show that Pax7 levels are maintained in proliferating muscle progenitors by a mechanism involving casein kinase 2-dependent Pax7 phosphorylation at S201. Point mutations preventing S201 phosphorylation or casein kinase 2 inhibition result in decreased Pax7 protein in proliferating muscle progenitors. Accordingly, this correlates directly with increased Pax7 ubiquitination. Finally, Pax7 down regulation induced by casein kinase 2 inhibition results in precocious myogenic induction, indicating early commitment to terminal differentiation. These observations highlight the critical role of post translational regulation of Pax7 as a molecular switch controlling muscle progenitor fate.

The different fate of satellite cells on conductive composite electrospun nanofibers with graphene and graphene oxide nanosheets

Electrospinning of composite polymer solutions provides fantastic potential to prepare novel nanofibers for use in a variety of applications. The addition of graphene (G) and graphene oxide (GO) nanosheets to bioactive polymers was found to enhance their conductivity and biocompatibility. Composite conductive nanofibers of polyaniline (PANI) and polyacrylonitrile (PAN) with G and GO nanosheets were prepared by an electrospinning process. The fabricated membranes were investigated by physical and chemical examinations including scanning electron microscopy (SEM), Raman spectroscopy, x-ray diffraction (XRD) and tensile assay. The muscle satellite cells enriched by a pre-plating technique were cultured in the following and their proliferation and differentiation behavior studied by MTT, Real-Time PCR assays and 4′, 6-diamidino-2-phenylindole (DAPI) staining. The cultured cells on composite nanofibrous PAN/PANI-CSA/G confirmed a higher proliferation and differentiation value compared to other groups including PAN/PANI-CSA/GO and PAN/PANI-CSA scaffolds. Furthermore, the higher stiffness of the former scaffold showed a lower cell spreading as a function of stem cell activation into more proliferative cells. It is supposed that the enhanced conductivity value in addition to relative higher stiffness of the PAN/PANI-CSA/G composite nanofibers plays a favorable role for proliferation and differentiation of satellite cells.

Molecular circuitry of stem cell fate in skeletal muscle regeneration, ageing and disease

Satellite cells are adult myogenic stem cells that repair damaged muscle. The enduring capacity for muscle regeneration requires efficient satellite cell expansion after injury, their differentiation to produce myoblasts that can reconstitute damaged fibres and their self-renewal to replenish the muscle stem cell pool for subsequent rounds of injury and repair. Emerging studies indicate that misregulation of satellite cell fate and function can contribute to age-associated muscle dysfunction and influence the severity of muscle diseases, including Duchenne muscular dystrophy (DMD). It has also become apparent that satellite cell fate during muscle regeneration and ageing, and in the context of DMD, is governed by an intricate network of intrinsic and extrinsic regulators. Targeted manipulation of this network may offer unique opportunities for muscle regenerative medicine.

Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells

Compensatory growth and regeneration of skeletal muscle is dependent on the resident stem cell population, satellite cells (SCs). Self-renewal and maintenance of the SC niche is coordinated by the paired-box transcription factor Pax7, and yet continued expression of this protein inhibits the myoblast differentiation program. As such, the reduction or removal of Pax7 may denote a key prerequisite for SCs to abandon self-renewal and acquire differentiation competence. Here, we identify caspase 3 cleavage inactivation of Pax7 as a crucial step for terminating the self-renewal process. Inhibition of caspase 3 results in elevated Pax7 protein and SC self-renewal, whereas caspase activation leads to Pax7 cleavage and initiation of the myogenic differentiation program. Moreover, in vivo inhibition of caspase 3 activity leads to a profound disruption in skeletal muscle regeneration with an accumulation of SCs within the niche. We have also noted that casein kinase 2 (CK2)-directed phosphorylation of Pax7 attenuates caspase-directed cleavage. Together, these results demonstrate that SC fate is dependent on opposing posttranslational modifications of the Pax7 protein.

The effect of temperature on apoptosis and adipogenesis on skeletal muscle satellite cells derived from different muscle types.

Satellite cells are multipotential stem cells that mediate postnatal muscle growth and respond differently to temperature based upon aerobic versus anaerobic fiber-type origin. The objective of this study was to determine how temperatures below and above the control, 38°C, affect the fate of satellite cells isolated from the anaerobic pectoralis major (p. major) or mixed fiber biceps femoris (b. femoris). At all sampling times, p. major and b. femoris cells accumulated less lipid when incubated at low temperatures and more lipid at elevated temperatures compared to the control. Satellite cells isolated from the p. major were more sensitive to temperature as they accumulated more lipid at elevated temperatures compared to b. femoris cells. Expression of adipogenic genes, CCAAT/enhancer-binding protein β (C/EBPβ) and proliferator-activated receptor gamma (PPARγ) were different within satellite cells isolated from the p. major or b. femoris. At 72 h of proliferation, C/EBPβ expression increased with increasing temperature in both cell types, while PPARγ expression decreased with increasing temperature in p. major satellite cells. At 48 h of differentiation, both C/EBPβ and PPARγ expression increased in the p. major and decreased in the b. femoris, with increasing temperature. Flow cytometry measured apoptotic markers for early apoptosis (Annexin-V-PE) or late apoptosis (7-AAD), showing less than 1% of apoptotic satellite cells throughout all experimental conditions, therefore, apoptosis was considered biologically not significant. The results support that anaerobic p. major satellite cells are more predisposed to adipogenic conversion than aerobic b. femoris cells when thermally challenged.

NEDD4 Regulates PAX7 Levels Promoting Activation of the Differentiation Program in Skeletal Muscle Precursors.

The transcription factor Pax7 regulates skeletal muscle stem cell (satellite cells) specification and maintenance through various mechanisms, including repressing the activity of the muscle regulatory factor MyoD. Hence, Pax7-to-MyoD protein ratios can determine maintenance of the committed-undifferentiated state or activation of the differentiation program. Pax7 expression decreases sharply in differentiating myoblasts but is maintained in cells (re)acquiring quiescence, yet the mechanisms regulating Pax7 levels based on differentiation status are not well understood. Here we show that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4. Our results indicate that Nedd4 is expressed in quiescent and activated satellite cells, that Nedd4 and Pax7 physically interact during early muscle differentiation-correlating with Pax7 ubiquitination and decline-and that Nedd4 loss of function prevented this effect. Furthermore, even transient nuclear accumulation of Nedd4 induced a drop in Pax7 levels and precocious muscle differentiation. Consequently, we propose that Nedd4 functions as a novel Pax7 regulator, which activity is temporally and spatially controlled to modulate the Pax7 protein levels and therefore satellite cell fate.

FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration.

Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue.

RNA-Seq analysis of isolated satellite cells in Prmt5 deficient mice.

Satellite cells (SCs) represent a distinct population of stem cells, essential for maintenance, growth and regeneration of adult skeletal muscle. SCs are mononuclear and are located between the basal lamina and the plasma membrane of myofibers. They are typically characterized by presence of the transcription factor paired-box 7 (PAX7) that is widely used as a satellite cell marker. Under normal physiological conditions SCs are quiescent but are activated by insults such as injury, disease or exercise. Once activated, satellite cells proliferate and subsequently differentiate into myoblasts to finally fuse to form new myofibers or with preexisting myofibers to repair or rebuild the skeletal muscle. A minority of SCs retains stem cell characteristics and self-renews to assure future bouts of regeneration throughout most of adult life. While a comprehensive picture of the regulatory events controlling SC fate has not yet been achieved, several factors were recently identified playing important roles in functional processes. One example is the arginine methyltransferase Prmt5 that is known to have multiple roles in germ cells and is involved in the maintenance of ES cell pluripotency. We have previously shown that Prmt5 is required for muscle stem cell proliferation and regenerative myogenesis due to direct epigenetic regulation of the cell cycle inhibitor p21. Here we provide a dataset that investigates the loss of Prmt5 in isolated Pax7+ primary SCs using the Pax7CreERT2/Prmt5loxP/loxP knockout mouse model.RNA-Seq raw and analyzed data have been deposited in GEO under accession code GSE66822.

Intrinsic and extrinsic mechanisms regulating satellite cell function.

Muscle stem cells, termed satellite cells, are crucial for skeletal muscle growth and regeneration. In healthy adult muscle, satellite cells are quiescent but poised for activation. During muscle regeneration, activated satellite cells transiently re-enter the cell cycle to proliferate and subsequently exit the cell cycle to differentiate or self-renew. Recent studies have demonstrated that satellite cells are heterogeneous and that subpopulations of satellite stem cells are able to perform asymmetric divisions to generate myogenic progenitors or symmetric divisions to expand the satellite cell pool. Thus, a complex balance between extrinsic cues and intrinsic regulatory mechanisms is needed to tightly control satellite cell cycle progression and cell fate determination. Defects in satellite cell regulation or in their niche, as observed in degenerative conditions such as aging, can impair muscle regeneration. Here, we review recent discoveries of the intrinsic and extrinsic factors that regulate satellite cell behaviour in regenerating and degenerating muscles.

The altered fate of aging satellite cells is determined by signaling and epigenetic changes.

Skeletal muscle is a striated tissue composed of multinucleated fibers that contract under the control of the somatic nervous system to direct movement. The stem cells of skeletal muscle, known as satellite cells, are responsible for muscle fiber growth, turnover, and regeneration. Satellite cells are activated and proliferate in response to stimuli, and simplistically, have two main fates—to repopulate the satellite cell niche, or differentiate to regenerate or repair muscle fibers. However, the ability to regenerate muscle and replace lost myofibers declines with age. This loss of function may be a result of extrinsic changes in the niche, such as alterations in signaling or modifications to the extracellular matrix. However, intrinsic epigenetic changes within satellite cells may also affect cell fate and cause a decline in regenerative capacity. This review will describe the mechanisms that regulate cell fate decisions in adult skeletal muscle, and how changes during aging affect muscle fiber turnover and regeneration.

Muscle stem cell fate is controlled by the cell-polarity protein Scrib.

Satellite cells are resident skeletal muscle stem cells that supply myonuclei for homeostasis, hypertrophy, and repair in adult muscle. Scrib is one of the major cell-polarity proteins, acting as a potent tumor suppressor in epithelial cells. Here, we show that Scrib also controls satellite-cell-fate decisions in adult mice. Scrib is undetectable in quiescent cells but becomes expressed during activation. Scrib isasymmetrically distributed in dividing daughter cells, with robust accumulation in cells committed to myogenic differentiation. Low Scrib expression is associated with the proliferative state and preventing self-renewal, whereas high Scrib levels reduce satellite cell proliferation. Satellite-cell-specific knockout of Scrib in mice causes a drastic andinsurmountable defect in muscle regeneration. Thus, Scrib is a regulator of tissue stem cells, controlling population expansion and self-renewal with Scrib expression dynamics directing satellite cell fate.