Bioenergetics mechanisms regulating muscle stem cell self-renewal commitment and function

Bioenergetics mechanisms regulating muscle stem cell self-renewal commitment and function

Biomedicine & Pharmacotherapy 103 (2018) 463–472 Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsev...

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Biomedicine & Pharmacotherapy 103 (2018) 463–472

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha

Review

Bioenergetics mechanisms regulating muscle stem cell self-renewal commitment and function

T

Phablo Abreu Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Av. Prof. Lineu Prestes, 748 – Butantã, São Paulo, CEP: 05508-000, SP, Brazil

A R T I C LE I N FO

A B S T R A C T

Keywords: Adult muscle stem cell Metabolic control Cell fate

Muscle stem cells or satellite cells are crucial for muscle maintenance and repair. These cells are mitotically quiescent and uniformly express the transcription factor Pax7, intermittently entering the cell cycle to give rise to daughter myogenic precursors cells and fuse with neighboring myofibers or self-renew, replenishing the stem cell pool in adult skeletal muscle. Pivotal roles of muscle stem cells in muscle repair have been uncovered, but it still remains unclear how muscle stem cell self-renewal is molecularly regulated and how muscle stem cells maintain muscle tissue homeostasis. Defects in muscle stem cell regulation to maintain/return to quiescence and self-renew are observed in degenerative conditions such as aging and neuromuscular disease. Recent works has suggested the existence of metabolic regulation and mitochondrial alterations in muscle stem cells, influencing the self-renewal commitment and function. Here I present a brief overview of recent understanding of how metabolic reprogramming governs self-renewal commitment, which is essential for conservation of muscle satellite cell pools throughout life, as well as the implications for regenerative medicine.

1. Introduction

regenerative medicine and related cell therapies.

Muscle stem cells or satellite cells are stem cells required for muscle development, repair and tissue conservation. In adult muscle under normal conditions, these cells represent 3–5% of the overall amount of fiber nuclei [1]. The capacity to self-renew under normal physical conditions is essential to maintain the number of muscle stem cells to contribute toward repetitive muscle repair and to ensure the life-long preservation of contractile tissue. In response to muscle damage, such as injury, toxins, diseases or exercise, quiescent muscle stem cells (a state termed G0) are activated and undergo a highly orchestrated activity with intense proliferation which gives rise to committed muscle precursors [2,3]. Recent work has observed that muscle stem cell activation can be regulated through metabolism. Thus, regulating metabolism may determine cell fate, and could be a successful strategy for understanding progressive muscle diseases and sarcopenia during aging [4,5,6,7]. The function of metabolism in adjusting cell commitment and function through transcription and post-transcriptional factors have been called “metabolic reprogramming” and represent a rising field of investigation [4,5,7]. My focus on this brief overview is to present recent understanding of the regulatory metabolic mechanisms governing muscle stem cell selfrenewal commitment, which is essential for conservation of this cells as a stem cells pool throughout life, as well as implications for

2. Cytoskeletal architecture and muscle stem cells

E-mail address: [email protected] https://doi.org/10.1016/j.biopha.2018.04.036 Received 22 February 2018; Received in revised form 4 April 2018; Accepted 5 April 2018 0753-3322/ © 2018 Published by Elsevier Masson SAS.

Skeletal muscle is one of the most dynamic and fascinating tissues with a complex structure. It’s attached to the bone and forms a distinct organ, including its cytoskeletal architecture, excitation-contraction coupling and energy metabolism. In this sense, Alexander Mauro [1] correctly predicted the origin and role of muscle stem cells, due their sub laminar location and intimate association with blood vessels and myofiber nuclei, as remnants of embryonic growth, organized to repeat this process following muscle damage [1] (Fig. 1). Current conclusions demonstrate that the activation of muscle stem cells during muscle regeneration is strongly influenced by the environment, such as nutrition and exercise [3,4,5,6]. Adult muscle satellite cells are characterized by the expression of paired domain transcription factor Pax7, which plays a key function in maintaining the quiescence and proliferation of progenitors, blocking premature differentiation and apoptotic cell death. The ablation of Pax7 allows muscle stem cells to assume different cell fates, confirming their critical function in conserving the myogenic identity [8,9]. In addition, other markers can be observed by microscopy and have been used as markers of muscle stem cells, such as paired domain transcription factor Pax3, characterized in embryonic myogenic progenitors during myofiber formation and mouse fetal development [8,9]; myogenic

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Fig. 1. Structural overview of the various domains of skeletal muscle structure and muscle cross-sectional area. Muscle tissue is one of the most plastic tissues of the body, being attached to bones by structural proteins and connective tissues fibers. Multiple bundles of cells called skeletal muscle fibers or fascicles are surrounded by perimysium, a type of connective tissue, which contains myonuclei arranged in clusters surrounded by a high density of subsarcolemmal mitochondria next to capillary branches. Muscle fibers are in turn composed of myofibrils or muscle fibrils that are basic units of a muscle cell, forming the basic machinery necessary for muscle contraction. Muscle stem cells or satellite cells are found between the basement membrane and the sarcolemma of muscle fibers. In adult myofibers, these cells expressing paired box 7 (Pax7) are normally quiescent and have high levels of active mitochondria, but that can be activated by metabolic and structural process to provide additional myonuclei for muscle maintenance, growth or repair. These cells are preferentially localized next to blood vessels that provide key bioenergetics resources needed for cell proliferation during activation, modulating the surrounding microenvironment of satellite cell and function [1,2].

Fig. 2. Intracellular molecular markers and cell membrane surface for quiescence and activation muscle stem cells. The muscle stem cells can be identified by the specific intracellular expression of certain proteins, such as the transcription factors Pax7 and the nuclear membrane proteins lamin A/C and emerin, and specific markers located at the cell membrane surface such as syndecans 3 and 4 (Synd3/4), muscle M-cadherin (Mcad), calcitonin receptor (CalcR), C-X-C chemokine receptor type 4 (CXCR4), calveolin-1 (Cav1), α7- and β1-integrins (Itga7 and Itb1), neural cell adhesion molecule 1 (Ncam1), vascular cell adhesion molecule 1 (Vcam1) and CD34. The identification of these transcriptional factors improved the understanding of muscle stem cell function and commitment, furthering our ability to isolate muscle stem cell and modulate their behaviour in vivo to better control their quiescence and transition to activation state. With better purification methods and labelling for stem-cell-specific markers, several groups have developed cell-sorting techniques to prospectively isolate satellite cells, using a combination of positive selection for satellite cell surface markers and a negative selection for hematopoietic and fibrogenic lineages. Taken together, recent molecular and genetic studies of muscle stem cells are imperative to gain a holistic understanding of adult myogenesis and to enhance the regenerative capacity of damaged muscles. Adapted by Yin et al. [12].

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regulatory factors myogenic regulatory factor Myf5 and/or myogenic differentiation MyoD (also known as MyoD1), followed by Myogenin and MRF4, resulting in the formation of skeletal muscle compartments following injury or growth stimulus in adult skeletal muscle [10,11,12]; tyrosine receptor kinase c-Met expressed in adult quiescent muscle stem cells, throughout myoblast activation and myocyte differentiation [13]; homeobox transcription factor Barx2 that regulates the plasticity for normal skeletal muscle growth and repair [14,15]; cell adhesion protein M-cadherin that plays an important role in cell-to-cell recognition and fusion, and is crucial for cell division activation [16]; cell surface attachment receptor α7-integrin (Itga7) and β1-integrin (Itb1) involved in the migration and proliferation of myoblasts, the formation and integrity of neuromuscular junctions [17]; cluster of differentiation protein CD34 that reveals a role in promoting efficient myogenic progression in muscle regeneration, specifically in satellite cell migration and entry into cell cycle. [18]; transmembrane heparin sulfate proteoglycans Syndecan-3/4 (Synd-3/4) that play important regulatory roles in satellite cell maintenance and activation during skeletal muscle regeneration [19]; chemokine receptor CXCR4, like CD34+ cells, display this receptor on their surface by muscle stem cells [20]; protein Caveolin-1 (Cav1) is expressed in satellite cells but not in mature muscle fibres, modulating the muscle stem cell activation during muscle repair [21]; receptor of Calcitonin (CalcR) was specifically expressed on quiescent or dormant muscle stem cells but not in activated/proliferating muscle stem cells during muscle regeneration [22]; nuclear envelope proteins Lamin A/C and Emerin, both were also expressed in both quiescent and proliferating satellite cells [23]; receptor Frizzled (Fzd) for Wnt signaling proteins that is activated by Wnt/β-catenin and Wnt/planar cell polarization (PCP) pathways [24]; transmembrane receptor Notch, that regulates cell expansion and cell fate determination, been activated by the binding of Delta and Jagged family, the result of which induces cleavage of the Notch receptor and release of an active truncated form of Notch intracellular domain (NICD), translocates from the cytoplasm to the nucleus and activates the gene expression [25]; vascular cell adhesion protein Vcam1, is present on myoblasts and myotubes, which suggest that interaction influence alignment of secondary myoblasts along primary myotubes and inhibit myotube formation in culture [26]; and neural cell adhesion molecule Ncam1, that your expression to be coincident with the earliest detectable markers of commitment to differentiation of adult myoblasts and myocytes [27] (Fig. 2). In this context, the identification of MyoD, a master transcription factor that can induce skeletal muscle differentiation and is one of the earliest markers of myogenic commitment, provided the initial evidence that a unique gene can initiate an intricate program of differentiation. This transcription factor is undetectable levels in quiescent satellite cells. The expressions of Myf5, followed by MyoD, are both mandatory for myogenic determination. Myogenin and MRF4 (Myf6) work downstream to activate progression to the myocyte primed for fusion with existing or newly formed myofibers and terminal differentiation. These bHLH (basic helix loop helix) transcription factors belong to a family of proteins known as myogenic regulatory factors (MRFs) [10,11,12] (Fig. 2). In summary, satellite cell activation is ordered by key mechanisms that determine the trade-off between expansion and differentiation. Besides the evidence and open questions, these mechanisms are starting to be better understood, accelerating potential advances of possible therapeutic interventions in muscle disorders (Table 1).

Table 1 Wide evidence and open questions over the last three decades have collected much insights and knowledge of muscle regeneration with a focus on satellite cells, along with a summary of the molecular processes governing satellite cell self-renewal and myogenic differentiation potential. Evidence Adult muscle stem cell exhibits a distinct phenotype and function, demonstrating that the stem cell population is heterogeneous. When and how the organization of daughter cell fate is controlled is still not completely understood. uscle stem cell activation is ordered by key mechanisms that determine the balance between differentiation and expansion through self-renewal. This understanding will facilitate the development of new therapies to expand muscle stem cells in vitro for transplantation and to enhance the regenerative capacity of damaged muscles. Understanding how muscle stem cell adjusts these processes of differentiation potential, gene expression signatures, stemness into microenvironment has important repercussions to provide new molecular targets for therapeutic intervention. The ability to maintain the content of muscle stem cells pool in respect to their cell fate potential is coordinated by a shift in the cellular metabolic state, an activity referred as metabolic reprogramming, constituting a very promising tool for regenerative medicine approaches.



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Open Questions In addition to the heterogeneity of this cell, when and how the intrinsic and extrinsic elements govern the muscle stem cell function and division? And command muscle muscle stem cell to generate the correct types and numbers of cells to preserve muscle tissue homeostasis and health? How intracellular mechanisms from the muscle stem cells niche synchronize and collaborate to guide satellite cell self-renewal versus cell differentiation and myogenic commitment? What factors interfere into balance between self-renewal and generation of post-mitotic progenitors over time to support the cell population? When and how the muscle stem cells fates switch their expansion throughout muscle repair and, appropriately, regulate the cell cycle? Not only preserving the stem cell population but also providing numerous new myofibers that reconstitute a functional contractile apparatus? What are the cellular energy requirements is needed, generated via oxidative phosphorylation in the mitochondria and glycolysis in the cytoplasm, during the transition from quiescence to muscle stem cell activation that driving cell commitment? How metabolic reprogramming provides energy to cell quiescence, activation, proliferation, differentiation and fusion into myotubes/myofibers? How nutrient availability, exercise, hypoxia, oxidative stress, inflammation and aging can influence the cell fate? How the metabolism sensors, such as AMPK, NAD-dependent protein deacetylase SIRT1, PGC-1α and FOXO, that regulate mitochondrial metabolism and enhance the myogenic function, that can to lead to higher transplantation efficiency in recipient mice?



• • • • •

AMPK = 5′ AMP-activated protein kinase or AMPK or 5′ adenosine monophosphate-activated protein kinase; NAD = Nicotinamide adenine dinucleotide; SIRT = Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1; PGC-1α = Peroxisome proliferator-activated receptor gamma coactivator 1alpha; FOXO = Forkhead box O.

stem cell pool, while augmented asymmetric divisions favor myogenic progenitor differentiation. When and how the organization of daughter cell fate is controlled is not well comprehended. Kuang and collaborators observed that orientation of the mitotic spindle relative to the myofiber axis correlates with daughter cell destiny. The authors demonstrated that satellite cells expressing Pax7+, but not Myf5+, give rise to Myf5-expressing cells through sublaminar cell divisions in a basal-apical orientation or asymmetric division, confirming that Pax7+/Myf5+ satellite cells preferentially differentiate, whereas Pax7+/Myf5− cells contribute to the expansion of the muscle stem cell pool. Additionally, the daughter cells committed to myogenic lineages present high levels of Delta1, while daughter muscle stem cell express Notch3 receptors and promote the return to a quiescence state. Altogether, theses authors reported the existence of heterogeneous population of muscle satellite cells and committed myogenic progenitors, that are distinct in phenotype and function [28]. Carm1 is required for Myf5 transcription during asymmetric cell division, which regulates muscle stem cell entry into the myogenic

3. Cell cycle regulation and muscle stem cell self-renewal commitment Muscle stem cells can undergo both symmetric and asymmetric division, showing that these muscle cell populations are heterogeneous and exhibit distinct phenotypes as well as different functions. Increased symmetric division supports expansion and conservation of the muscle 465

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Fig. 3. Regulation of the muscle stem cell commitment and the maintenance of the cell pool in adult muscle. Pax7 progenitor cells readily enter the cell cycle and undergo proliferation, differentiation and undergo cell-to-cell fusion to repair damaged myofibers or form nascent multinucleated myofibers. While a small part do this in a much slower manner, withdrawing from the cell cycle and becoming satellite cells or muscle stem cells. The transition from muscle stem cell activation to quiescence is orchestrated by key transcription factors that dictate the return to the cell compartment through self-renewal divisions to replenish and expand their population in response to acute need for a large number of satellite cells after injury or disease state. The muscle stem cells undergo dynamic transitions between functional phases in the quiescent stat. A pre-activated state between the G0 quiescent and activated state referred to as GAlert, satellite cells then re-enter the cell cycle and return to quiescence state.

progression of muscle progenitors to differentiation commitment and mature myofibers. In addition, Bentzinger and collaborators have demonstrated that, during muscle repair, the niche of satellite cells was transiently remodeled by extracellular matrix (ECM) fibronectin into their microenvironment, forming a Synd-4 and Fzd7 receptor complex for Wnt7a in activated satellite cells and inducing the expansion of the muscle stem cell pool. The knockdown of fibronectin leads to an intense reduction of the satellite cell numbers, impairing their ability to repopulate the muscle stem cell niche [37]. Together, theses studies demonstrated that newly activated satellite cells dynamically remodel their niche during muscle repair, modulating their expansion within their niche to induce the symmetric expansion of satellite stem cells. Meticulous regulation of the cell cycle is critical to ensure suitable development through several overlapping conditions. A hallmark of muscle satellite cells is the capability to self-renew and return to quiescence or the G0 state (reversibility) and the maintenance of this ability is essential to replenish the satellite cell pool and muscle homeostasis [33,34]. In addition to proliferation and differentiation of muscle satellite cell, activated cells also have a significant role in preserve their own stem cell reserve pool through self-renewal. In this sense, the maintenance of cells is essential for continuous muscle repair, especially in muscular dystrophy and aging muscle. Although the molecular mechanisms of how satellite cells maintain their numbers or functions is not completely understood throughout the life. Therefore, the understanding of how muscle satellite cells adjust to these procedures into their microenvironment has important repercussions for regenerative medicine and to provide new molecular targets for therapeutic intervention and pharmacological manipulation [35,36]. Altogether, theses works showed the mechanisms by which muscle stem cells maintain the precise balance between self-renewal and differentiation and pool heterogeneity during developmental myogenesis necessary for long-term homeostasis (Fig. 3). With the advent of RNA sequencing technology, the investigation of transcriptome profiles of different muscle satellite cells states has been greatly enhanced [37]. However, little is known about the induction of quiescence. Cell cycle inhibitors are well-known modulators of stem cell fate within this quiescence signature, including cyclin-dependent kinase inhibitors 1 C (p57kip2 also known as CDKN1C) and 1B (p27kip1 also known as CDKN1B), p21Cip1 (alternatively p21Waf1 also known as

program. Fully, in this study, they investigated the mechanism that regulates the activity of Pax7 during satellite stem cell asymmetric cell division and found that Pax7 is a specific substrate of Carm1, and that Carm1 methylation of Pax7 is required as a molecular switch, controlling the epigenetic induction of Myf5 transcription, to regulate satellite stem cell entry into the myogenic program, providing insight into the molecular mechanisms that regulate the specification of stem cells [29]. On the other hand, symmetric division stimulated by Wnt receptor Fzd-Wnt7a promotes activation of the planar cell polarity (PCP) effector Vang-like protein 2 (Vangl2) pathway, but does not affect the growth or differentiation of myoblasts, revealing a function for PCP signaling in regulating the homeostatic maintenance of the muscle stem cell pool and return to the quiescent state during adult skeletal muscle repair. Wholly, these results reveal a role for the PCP pathway in regulating the homeostatic maintenance of the stem cell compartment during adult skeletal muscle regeneration, providing important advance in our understanding of satellite cell biology and insights into the molecular mechanisms regulating their function in regulating the symmetric expansion of satellite stem cells [30]. The Wnt pathway does not require the transcriptional activity of βcatenin, however it includes the activation of Fzd, Vangl, Dsh and Prickle markers [31,32]. TWnt + pathway activation by the Fzd receptor leads to the release of intracellular Ca2+, leading to activation of the transcription factor nuclear factor of activated T cell (NFAT) [33]. Additionally, the activation of PI3K/AKT/ mammalian target of rapamycin (mTOR) signaling by the Wnt pathway resulted in muscle protein synthesis and fiber growth [34]. Entirely, these reports demonstrated that Wnt7a-Fzd7 activates distinct pathways at different developmental stages during myogenic lineage progression, driving the symmetric expansion of satellite stem cells resulting in enhanced repair of skeletal muscle and providing a promising new therapeutic focus for the amelioration of muscle wasting diseases. Symmetric muscle stem cell divisions stimulated by pharmacological inhibition of the JAK-STAT pathway enhance satellite cell proliferation in dystrophic and aged mice [35]. Nevertheless, the expansion of differentiated muscle progeny was coordinated by Wnt3a and transforming growth factor (TGFβ) during regeneration of muscle tissue [36]. In this work, the passage from Notch signaling to Wnt occurs via Glycogen synthase kinase 3 beta (GSK3 beta), which promotes the 466

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cells and for the maintenance of satellite cell self-renewal [50]. Altogether, these findings have implications for the roles of Numb and Hesr family genes in the maintenance of tissue homeostasis, cell fate specification and facilitate investigation of the molecular regulation of satellite cells, and the promotion of myogenic differentiation. In mammals, the stem cell niche is a critical factor in the maintenance of quiescence during homeostasis. In this sense, the over-expression of basic fibroblast growth factor 2, also known as bFGF, FGF2 or FGF-β, promotes a muscle stem cell content reduction and impaired regenerative capacity [43]. Added to this, the conditional knockout of CDKN1B results in precocious activation of quiescent muscle stem cells and aberrant satellite cell proliferation, and thereby adult satellite cell pool size during tissue turnover [44]. In this context, the increased expression of sprouty 1 (Spry1), an inhibitor of FGF2 signalling, is critical for satellite cell reversible quiescence, increasing their self-renewing capability and contributing to myofiber regeneration [51]. Briefly, the role of Spry1and FGF, revealed that appropriate regulation of reversible quiescence is essential for self-renewal of the adult Pax7, replenishing the renewed satellite cell pool and contributing to myofiber repair. The Mitogen Activated Protein Kinases (MAPKs) pathway is expressed in muscle stem cells activated during the G1 phase of the cell cycle. The inhibition of this MAPK signaling stimulates muscle stem cell proliferation and the reversible quiescent state in adult muscle, making it an important biological tool for muscle repair and maintenance of the tissue [52]. Additionally, Troy and co-workers have observed that the p38α/β MAPK pathway is amplified during differentiation of muscle satellite cells leading to induction of MyoD expression, regulating cell fate commitment to myogenesis [53]. In general, the activation of the skeletal muscle satellite cell is concomitant with the activation of p38α/ β MAPKs and suggest that these MAPKs function as a molecular switch determining the activation state of the satellite cell, ensuring that sufficient numbers of satellite cells self-renew and preserving the stem cell population for the continued maintenance and repair of skeletal muscle tissue. The maintenance of satellite cell niches may be influenced by the interaction with endothelial cells. Christov and collaborators have demonstrated an intimate connection of quiescent muscle stem cells with micro vessels positioned near capillaries in their sublaminal niche. The authors observed that myogenic progenitors were associated with new vessel growth in muscle dystrophy [54]. Vascular homeostasis and integrity can be regulated by angiopoietin 1 (Ang1) that binds to its tyrosine kinase Tie-2 endothelial receptor (Tie2). The autocrine and paracrine Ang1/Tie2 signaling exerts its effect through the ERK1/2 pathway that is involved regulation of myogenic cell fate and muscle stem cell self-renewal [55]. These findings suggest that quiescent satellite cells are juxtavascular, tightly associated with the myofiber in their sublaminal niche without loosing this anatomical characteristic, and are prepositioned near capillaries and associated with new vessel formation, regardless of their state of quiescence or activated. The collagen VI is the major ECM protein, and is extensively remodeled during muscle regeneration. Urciuolo and colleagues have shown that collagen VI is a critical component of muscle stem cell niche proteins that maintain the satellite cell pool, essential for conserving self-renewal of satellite cells and muscle regeneration. Collagen VI null (Col6a1–/–) mice have a lower mean myofiber cross-sectional area and a lower ability to preserve the Pax7+MyoD− population. Taken together, these results show that collagen VI improves the survival of cells expressing Pax7, a transcription factor critical for muscle stem cell selfrenewal after damage and muscle stiffness, providing insights into the relevance of collagen VI for skeletal muscles and reveal an unforeseen role for this ECM molecule in the regulation of muscle stem cell homeostasis [56]. The quiescent muscle satellite cells are also post-transcriptionally regulated by microRNAs (miRNAs) [57,58]. Deleting the Dicer enzyme in adult muscle diminishes the number of cells and severely impairs the

CDK1), retinoblastoma protein (pRb and its gene RB or RB1), a novel family of GTPase-activating proteins that rapidly turn-off G-protein coupled receptor signaling (RGS-2 and RGS-5) and the integral membrane protein called peripheral myelin protein 22 (PMP22) affect stem cell function and self-renewal capability, preventing the precocious activation of quiescent muscle satellite cells and conservation of the primitive state and self-renewal potential [38,39,40,41,42,45]. Entirely, the markers provide new insight into how these cells orchestrate their own maintenance and protection as quiescent satellite cells, as well as controls the muscle fiber remodeling for efficient regeneration within the niche when these cells to leave the niche to become activated. Rando's group [38], show that Notch signaling is expressed by quiescent muscle stem cell and features prominently in modulation of activated muscle stem cell expansion and declines progressively as these myogenic cells differentiate. The downstream targets of Notch signaling, Hes1, Hey1 and HeyL, and their ligands (transmembrane proteins) Delta-like1, Delta-like4, Jagged1, and Jagged2 are highly expressed at the transcriptional level in quiescent muscle satellite cells. Furthermore, recombining binding protein suppressor of hairless (RBPJ), also known as CBF1, is a central mediator of Notch signaling and acts downstream of receptors which are required to maintain the satellite cells in a state of quiescence by preventing satellite cell activation in adults, demonstrating that Notch signaling plays a function in the regulation of satellite cell quiescence in muscle tissues. In this sense, Tajbakhsh's group [46] demonstrated that Notch is active and sufficient to autonomously maintain and self-renew muscle stem cells, in spite of the complete abrogation of committed cells, throughout development in the muscle founder stem cell population. In this way, in addition to regulating proliferative expansion of activated muscle stem cell, Notch may also be important in the regulation of satellite cell quiescence and was sufficient to allow their maintenance, temporal specification and recapitulation of ontology in the absence of committed progeny and differentiation. Synd-3, a transmembrane protein that acts as a co-receptor, especially for G protein-coupled receptors, is constituent of the satellite cell niche that interacts with Notch signaling playing a role in satellite cell homeostasis. This protein interacts with extracellular matrix proteins and growth factors, affecting skeletal muscle regeneration, supporting Synd-3 and Notch ligand Delta1 regulation of myofiber size [47]. In general way, exploring the mechanisms involved in Synd-3–mediated regulation of adult myogenesis and interactions with Notch, the absence of Synd-3 impairs Notch signaling, altering muscle stem cell homeostasis and affecting skeletal muscle regeneration. The lineage of forkhead transcriptional factors (FOXO) downstream of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, also known as AKT), pathway adjusts an extensive diversity of physiological processes, regulating stem cell and cell cycling in many tissues. In adult muscle tissue, Gopinath and co-workers, have observed that FOXO3 is essential for the self-renewal, preventing premature terminal differentiation and maintenance satellite cells in the quiescent state during muscle repair, by regulating the Notch signaling pathway [48]. Taken together, these results evidence a requirement for FOXO3 as a regulator of Notch signaling in the self-renewal of muscle stem cells in the context of the proliferation and differentiation during muscle repair. The Notch pathway also mediates local cell-cell interactions and cell fate determination, delaying differentiation. Conboy & Rando, have shown that Notch-1 controls the proliferation of myogenic progenitor cells, suggesting that the activation of Notch1 is important for the expansion of muscle progenitor cells (Pax3+ and M-cadherin+), and the inhibition of myogenic regulated factors (MRFs) and desmin expression. The reduction of Notch1 expression by Numb results in the progression of myogenesis from myoblast expansion to myogenic commitment and differentiation, showing new insights into the self-renewal properties of muscle satellite cells [49]. Hesr1 and Hesr3 are important regulators of target genes of Notch pathway, responsible for undifferentiated satellite 467

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growth. In this sense, the nutrient sensor SIRT1 promotes bioenergetics muscle stem cell activation and regulates the autophagic flux in response to a relative lack of nutrient availability through the AMP-activated protein kinase (AMPK) pathway [7]. Pax7-specific SIRT1 knockout in satellite cells results in a phenotype similar to that observed when autophagy was inhibited. This contributes to the evidence that SIRT1 plays a critical secondary role in cellular bioenergetics for the generation of ATP and activation kinetics of quiescent satellite cells, suggesting the contribution of the NAD+-dependent SIRT1 deacetylase in promoting epigenetic changes required for muscle stem cell activation, promoting muscle cell differentiation through transcriptional regulation of target genes, partly via reduction in SIRT1-mediated H4K16 deacetylation on the MyoD promoter [4,5,7]. Summarizing, this study observed the role of autophagy in activation of muscle stem cells and that this activation is associated with a increase in cellular SIRT1, followed by ATP in order to generate nutrients for synthetic activity associated with the activation process. Rodgers and collaborators have characterized quiescence in two distinct states: (1) G0 and (2) the “alert” phase, termed GAlert. Intriguingly, the quiescent functional properties of non-injured contralateral hindlimb related to injury or non-injured hindlimb muscle was phenotypically different from classical G0 state. GAlert presents upregulation of cell cycle genes transcriptional activity, elevated mitochondrial activity and oxidative phosphorylation. The authors have also observed that conditional ablation of the HGF receptor (cMet), prevents the expression of phospho-S6 (pS6) and mTORC1 signalling [6]. Thus, the metabolic reprogramming serves a vital role in preserving stem cell function and seems to be essential for enhancements in muscle regenerative ability and the engraftment of transplanted satellite cells [4,58,66]. These beneficial metabolic effects that favor muscle regenerative function were also investigated in hypoxic conditions, which maintain their stemness and play a fundamental function in self-renewal through Pax7 upregulation and expression of two Notch target genes (Hes1 and Hey1). Myogenic differentiation was inhibited, enhancing transplantation efficiency of hypoxia-conditioned myoblasts and therefore representing a candidate target for therapeutic intervention [63]. Likewise, the increase of muscle stem cell frequency through Pax7expressing satellite cells and myogenic function, in addition to transplantation efficiency, was improved following calorie restriction [4]. This enhanced myogenic activity observed by up-regulation of the Notch pathway was accompanied by metabolic reprogramming stimulated by increased of FOXO3 protein and NAD+-dependent SIRT1 deacetylase that promoted epigenetic environmental changes during local skeletal muscle tissue injury and repair, supported by NAD+ generation via mitochondrial oxidative phosphorylation under experimental conditions. Mitochondrial tricarboxylic acid cycle and oxidative phosphorylation pathways are downregulated in muscle satellite cells during senescence. Zhang et al., observed that NAD+ repletion, using a nutritional intervention, increased the number of muscle stem cells and muscle repair. In addition, muscle cells isolated from nicotinamide riboside-treated donors more effectively replenished the muscle satellite cells compartment and had enhanced transplantation efficiency [66]. Interestingly, the beneficial effect of nutritional treatment on mitochondrial metabolism and muscle regeneration after cardiotoxin injection appears to be attenuated in SIRT1MuSC−/− mice. In summary, the group demonstrated that mitochondrial activity regulated by NAD +-SIRT1 pathway (replenishing NAD + stores) is essential for the functional maintenance of the number and the self-renewal capacity of adult muscle stem cells during aging, being an attractive strategy for improving mammalian lifespan. Using C2C12 myoblasts, a reliance on glycolysis during cellular expansion and changes in bioenergetics were observed, with changes in substrate specification and differentiation with augmented

muscle repair [54]. This work highlighted a fundamental function of miRNAs in the preservation of satellite cell quiescence and proliferation of myogenic progenitors. The authors also demonstrated that the repression of Dek protein, a key target of miR-489, regulates the quiescent state and prevents the spontaneous activation of satellite cells [59]. Crist and colleagues studied the post-transcriptional mechanisms repress the translation of Myf5 mRNA in the quiescent muscle stem cells. When Myf5 satellite cells were activated, comparative concentrations of miR-31 were diminished [60]. These findings demonstrated a signaling network that regulates divergent fates of stem cell quiescence, being dependent upon the expression of specific miRNAs, so that muscle stem cells lacking miRNA pathway spontaneously exit quiescence and enter the cell cycle. In this context, Pax3, Pax7 and c-Met transcriptional factors were inhibited when the expression of miR-206 was increased in satellite cells, enhancing MyoD expression and muscle regeneration, reducing muscle fibrosis [61]. Similarly to miR-206, miR-1 is closely related in terms of expression, even though the function and specific targets are different [57,58]. The miR-206 and miR-1 promote myogenic differentiation, while miR-133 promotes myoblast proliferation and prevents cell differentiation [62]. This mechanism has a positive function in the treatment of skeletal muscle-related disorders. Taken with the previously mentioned cell-based studies, animal experiments and human research have demonstrated that miRNAs are involved in skeletal muscle development, growth/adaptation, regeneration and muscle-related diseases, becoming a potential therapeutic target for skeletal muscle diseases. Due to recent advances in cell and molecular biology, many factors, which control satellite cell cycle progression and the ability to maintain the content of muscle stem cells pool throughout different stages of adult myogenesis, have been discovered. These factors govern the function and cell fate decision, constituting a promising tool for regenerative medicine approaches, clinical applications and pharmacological manipulation. 4. Metabolic reprogramming of muscle stem cell fate Conceptually, under resting muscle conditions, quiescent muscle stem cells possesses reduced metabolic activity and deoxyribonucleic acid (DNA) replication, preserving cofactors and amino acids needed to support cellular growth during the activation of the cell cycle. A high demand for energy should be observed in response to muscle injury, which includes exercise, hypoxia, oxidative stress, inflammation and aging, which promoted a coordinated cellular bioenergetics reprograming. In summary, the remodeling of muscle stem cell activation is coordinated by a shift in the cellular metabolic state to match the functional requirements for cell fate decisions, an activity referred as metabolic reprogramming [3,4,5,6,7,63]. Ryall and colleagues observed metabolic reprogramming from fatty acid and pyruvate oxidation in quiescent muscle stem cells to glycolysis and glutaminolysis in activated muscle satellite cells. These changes were associated with a decrease of NAD+/NADH levels, reduction SIRT1-mediated deacetylation of H4K16ac, increases MyoD expression and no difference in basal oxygen consumption rates (OCR) and mitochondrial content. In Pax7-specific SIRT1 knockout mice (Sirt1muscle KO ) the percentage of Pax7+/MyoD+ satellite cells on fibers was increased and smaller fiber cross-sectional areas (CSA) are observed in response to cardiotoxin-induced muscle injury [5]. These results are consistent with a model in which the metabolic state influences the homeostasis and cell fate signaling in skeletal muscle, supporting the role of NAD+ and SIRT1 as a finely tuned biochemical sensor of the muscle stem cells metabolic state [4,5,7,64,65]. Altogether, these findings suggest a role for metabolism in the regulation of muscle satellite cell biology, and in process of metabolic reprogramming, transcriptional regulation, and acquisition of defined cell states, beyond simply providing the building blocks and ATP required for new cell 468

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progressive mitochondrial dysfunction and metabolic perturbation, which affects their regenerative ability [70]. An important link between optimal quality control of mitochondria and longevity was observed, assuring optimal mitochondrial turnover through synthesis and degradation is indispensible to muscle stem cell function [71]. Have been described that calorie restriction promotes an efficient autophagy process in age-associated diseases, through energetic sensors like FOXO1, FOXO3a, AMPK, mTORC1, SIRT3 and SIRT1, supporting a well-organized stem cell active [71,72,73,74]. In this sense, the endurance exercise on a treadmill can reduce the mitochondrial protein acetylation and promoted mitophagy which may accelerate organelle quality control, besides improvement of PGC-1α expression and increases the circulating levels of the NAD + precursor nicotinamide that are necessary for preventing muscle atrophy and function, which has a positive impact on aging-related conditions and impaired regeneration potential [75,76]. Thus, the understanding of fuel selection and mitochondrial oxidative efficiency as mechanisms linking enhanced exercise capacity with improved metabolic status and longevity, may providing important insights into the integration of signals in modulating the whole-animal response to exercise and aging. In old mice, the question of whether muscle stem cell numbers decrease with age was a long-standing controversy. Accumulating results indicates that regenerative potential of muscle satellite cells and selfrenewal capacity (return to quiescence) are impaired, have recently been proposed as main drivers of the decline in the muscle stem cell pool with aging [43]. This concept was powerfully reinforced by important results by Chakkalakal and group [43] demonstrating that muscle stem cell quiescence was disrupted during ageing under homeostatic conditions by increased expression of myofiber-derived fibroblast growth factor 2, leading to spontaneous mitogenic activity, diminution of the satellite cell pool, regenerative delay and reduction of the quiescent stem cell pool with aging by genetically removing Sprouty1. In aged Spry1null mice, the myofibre size of regenerated muscle was 50% smaller than the contralateral control, demonstrating that during regeneration blocking Fgfr1 signaling during ageing increases the self-renewal ability. In summary, the group investigated the influence of ageing on the satellite cell niche and its impact on satellite cell homeostasis and demonstrated that increased levels of FGF signaling directed from the aged satellite cell niche lead to the loss of

mitochondrial activity and content [67,68]. Glucose restriction impaired myoblasts differentiation through AMPK and SIRT1 enzymatic activation. In this sense, the cells are incapable of sustaining energydemanding processes that accompany differentiation, such as those associated with sarcomere assembly [4,5,7,69]. The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is activated by SIRT1 and AMPK. SIRT1 is a critical regulator of mitochondrial biogenesis and regulates energy expenditure in cultured myotubes by deacetylation of PGC-1α that provides a finely tuned amplification mechanism for energy homeostasis through fatty acid oxidation under low nutrient availability [64,65]. These studies have demonstrated that maintenance and self-renewal of muscle satellite cells through metabolic reprogramming may provide us the fundamental molecular mechanisms, which can be used in new therapeutic approaches for muscle disorders. In this way, briefly, the quiescent muscle satellite cells have a low metabolic rate and mitochondria activity, but in response to muscle injury (hypoxia, oxidative stress, inflammation, exercise, and aging), muscle stem cells become activated and trigger cellular reprogramming, regulating key pathways involved in cell fate commitment, providing a link between metabolic reprogramming and satellite cell activation (Fig. 4). Notwithstanding, the bioenergetics modifications observed in muscle stem cells can affect numerous molecular signaling pathways. This implies the existence of a system-wide metabolic response that primes satellite cells to become activated in a regenerative environment. Therefore, it will be interesting to assess whether this response is associated with exercise-induced training effects, calorie restriction or is altered in pathological conditions. Additional studies into the molecular events following metabolic changes in satellite cells are needed and will likely lead to the identification of novel cellular targets that regulate muscle stem cell behaviour, an important strategy to achieve successful treatments for muscle stem cell dysfunction and degenerative muscle diseases. 5. Metabolism, impaired muscle stem self-renewal and aging cell Muscle stem cell exhaustion and deficits in the capacity of regulate the cell cycle and cell fate decision during aging is generally linked to a

Fig. 4. Metabolic reprogramming of muscle stem cell, commitment and function. Metabolic reprogramming is referred to as a shift in the cellular metabolic status. During the transition from a quiescent to a proliferating state, muscle stem cells undergo extreme changes in size and metabolic activity. An increase in glycolysis may be required for satellite cell activation and expansion, while fatty acid and pyruvate oxidation is increased during exit from the cell cycle, both in the quiescent and differentiated state. Cell cycle exit promotes up-regulation of genes involved in oxidative phosphorylation and mitochondrial metabolism. Together, recent studies suggest that regulation of mitochondrial metabolism is a crucial aspect to appropriately balance self-renewal and commitment of myogenic progenitors. Metabolic reprogramming may also directly influence the capacity of these cells to maintain recovery from muscle injury and survival, as well as the effectiveness of their transplantation and ability of these cells to contribute to new and existing muscle fibres. 469

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potential and even prolonging organismal longevity.

quiescence and depletion of the resident stem cell population, inhibits satellite cell proliferation which eventually diminishes muscle regenerative capacity. In this way, strategies to prevent or repress FGF signaling at the level of the aged satellite cell may reduce skeletal muscle stem cell loss during ageing. In this sense, it has been revealed that muscle satellite cell-specific deletion of Sprouty1 in proliferating muscle stem cells leads to persistent activation of the extracellular-signal-regulated kinase/mitogenactivate protein kinase (ERK/MAPK) signaling pathway, which impairs self-renewal, and also the quality and fitness of each stem cell [51]. Thus, the muscle stem cells from aged mice fail to expand as efficiently and are more committed to differentiation (MyoD or Myogenin positive cells) when placed in culture. Bernet and coworkers [77] found increased p38α/β MAPK phosphorylation and MAPKAPK-2 (phospho–MK-2), a direct target of p38α/β MAPK, in myofiber-associated satellite cells from aged mice when compared with young mice. Additionally, the restoration of asymmetric phospho-p38 by partial inhibition of p38α/β MAPK suggests that self-renewal in muscle stem cell from aged mice may be similarly rescued, demonstrating that pharmacological manipulation of these pathways by enhancing FGFR1 signaling and reducing p38α/β MAPK activation to increase muscle satellite cell self-renewal can ameliorate age-associated skeletal muscle defects and to restore engraftment potential ability [77]. The treatment of muscle stem cells from young and older mice with drug inhibitors (pharmacological inhibition) of JAK-STAT signaling to determine their effect on engraftment potential and in vivo therapeutic approach to stimulate muscle regeneration was realized. The blocked expression of Jak2 or Stat3 increased the symmetric muscle stem cell differentiation in vitro and enhanced their capability to repopulate the satellite cell niche (number of Pax7+ satellite cells). Furthermore, a lower number of developmental myosin heavy chain fibers in the muscle of older mice treated with JAK-STAT signaling inhibitors, as well as a higher number of satellite cells that lacked MyoD expression (Pax7+MyoD−) or committed myogenic progenitors relative to vehicletreated controls was observed, resulting in enhancement of muscle regeneration, myofiber size, muscle stem cell numbers after cardiotoxin injury, likewise improves engraftment potential of young and aged satellite cells [35,78]. Altogether, this signaling activation prolonged promotes myogenic lineage progression, thereby inhibiting the expansion of the satellite cells during skeletal muscle repair and resulting from chronic degenerative stimuli might favor pro-differentiation pathways.

Conflicts of interest statement The author declares no conflict of interest. Funding This research was supported by the São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP) (process number 2016/18633-8), Research Center of Redox Processes in Biomedicine (Centro de Pesquisa, Inovação e Difusão de Processos Redox em Biomedicina - CEPID Redoxoma 2013/07937-8), and the Energy Metabolism Laboratory, Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), São Paulo-SP, Brazil. Acknowledgments I thank Dra. Alicia Kowaltowski for providing language help and proof reading the article; and Ms. Gislaine Chaves for help with illustration assistance and references. References [1] A. Mauro, Satellite cell of skeletal muscle fibers, J. Biophys. Biochem. Cytol. 9 (1961) 493–495. [2] T.H. Cheung, T.A. Rando, Molecular regulation of stem cell quiescence, Nat. Rev. Mol. Cell Biol. 14 (2013) 329–340. [3] P. Abreu, S.V. Mendes, V.M. Ceccatto, S.M. Hirabara, Satellite cell activation induced by aerobic muscle adaptation in response to endurance exercise in humans and rodents, Life Sci. 170 (2017) 33–40. [4] M. Cerletti, Y.C. Jang, L.W. Finley, M.C. Haigis, A.J. Wagers, Short-term calorie restriction enhances skeletal muscle stem cell function, Cell Stem Cell 10 (2012) 515–519. [5] J.G. Ryall, S. Dell’Orso, A. Derfoul, A. Juan, H. Zare, X. Feng, D. Clermont, M. Koulnis, G. Gutierrez-Cruz, M. Fulco, V. Sartorelli, The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells, Cell Stem Cell 16 (2015) 171–183. [6] J.T. Rodgers, K.Y. King, J.O. Brett, M.J. Cromie, G.W. Charville, K.K. Maguire, C. Brunson, N. Mastey, L. Liu, C.R. Tsai, M.A. Goodell, T.A. Rando, mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert), Nature 510 (2014) 393–396. [7] A.H. Tang, T.A. Rando, Induction of autophagy supports the bioenergetics demands of quiescent muscle stem cell activation, EMBO J. 33 (2014) 2782–2797. [8] S. Kuang, S.B. Charge, P. Seale, M. Huh, M.A. Rudnicki, Distinct roles for Pax7 and Pax3 in adult regenerative myogenesis, J. Cell Biol. 172 (2006) 103–113. [9] C. Lepper, S.J. Conway, C.M. Fan, Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements, Nature 460 (2009) 627–631. [10] K. Zhang, J. Sha, M.L. Harter, Activation of Cdc6 by MyoD is associated with the expansion of quiescent myogenic satellite cells, J. Cell Biol. 188 (2010) 39–48. [11] R.L. Davis, H. Weintraub, A.B. Lassar, Expression of a single transfected cDNA converts fibroblasts to myoblasts, Cell 51 (1987) 987–1000. [12] H. Yin, F. Price, M.A. Rudnicki, Satellite cells and the muscle stem cell niche, Physiol. Rev. 93 (1) (2013) 23–67. [13] M. Lindstrom, F. Pedrosa-Domellof, L.E. Thornell, Satellite cell heterogeneity with respect to expression of MyoD, myogenin, Dlk1 and c-Met in human skeletal muscle: application to a cohort of power lifters and sedentary men, Histochem. Cell Biol. (2010) 371–385. [14] R. Meech, M. Gomez, C. Woolley, M. Barro, J.A. Hulin, E.C. Walcott, J. Delgado, H.P. Makarenkova, The homeobox transcription factor Barx2 regulates plasticity of young primary myofibers, PLoS One (2010) e11612. [15] R. Meech, K.N. Gonzalez, M. Barro, A. Gromova, L. Zhuang, J.A. Hulin, H.P. Makarenkova, Barx2 is expressed in satellite cells and is required for normal muscle growth and regeneration, Stem Cells (2012) 253–265. [16] A. Irintchev, M. Zeschnigk, A. Starzinski-Powitz, A. Wernig, Expression pattern of M-cadherin in normal, denervated, and regenerating mouse muscles, Dev. Dyn. 199 (1994) 326–337. [17] D.J. Burkin, S.J. Kaufman, The alpha7 beta1 integrin in muscle development and disease, Cell Tissue Res. 296 (1999) 183–190. [18] L.A. Alfaro, S.A. Dick, A.L. Siegel, A.S. Anonuevo, K.M. McNagny, L.A. Megeney, D.D. Cornelison, F.M. Rossi, CD34 promotes satellite cell motility and entry into proliferation to facilitate efficient skeletal muscle regeneration, Stem Cells 29 (2011) 2030–2041. [19] F. Le Grand, R. Grifone, P. Mourikis, C. Houbron, C. Gigaud, J. Pujol, M. Maillet, G. Pagès, M. Rudnicki, S. Tajbakhsh, P. Maire, Six1 regulates stem cell repair potential and self-renewal during skeletal muscle regeneration, J. Cell Biol. 198 (2012) 815–832. [20] M.Z. Ratajczak, M. Majka, M. Kucia, J. Drukala, Z. Pietrzkowski, S. Peiper,

6. Concluding remarks and future perspectives Reports over the last three decades have accumulated knowledge, indicating that adjustments to the muscle stem cell activation requires a shift in the cellular bioenergetics state to better match their functional needs, a process referred as “metabolic reprogramming’’, resulting in satellite cells to maintain/return to quiescence, a process referred as self-renewal. These findings provide evidence for an effective therapeutic intervention for degenerative muscle disorders and muscle stem cell therapies to improve muscle regeneration and replenish the muscle stem cell pool. Notwithstanding muscle stem cells are presently not applicable to regenerative medicine due to complications in their isolation and loss of stemness ex vivo. Throughout muscle repair, the categorized and cooperative activities of muscle satellite cells are influenced by changes in diverse molecules, cells, and organizations that comprise an active niche constantly stimulating the numerous tasks set forth for muscle satellite cells. Nonetheless, the influence of metabolic reprogramming on intrinsic and extrinsic regulatory mechanisms that govern satellite cell commitment and differentiation, the age-related exhaustion of muscle stem cells and pharmacological inhibitors of intracellular pathways involved in these defects provide a proof-of-concept that opens up new therapeutic avenues and approaches for regenerative 470

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