Discovery of the myogenic regulatory factor family of transcription factors MYF5, MYOD, Myogenin and MRF4 was a seminal step in understanding specification of the skeletal muscle lineage and control ...of myogenic differentiation during development. These factors are also involved in specification of the muscle satellite cell lineage, which becomes the resident stem cell compartment inadult skeletal muscle. While MYF5, MYOD, Myogenin and MRF4 have subtle roles in mature muscle, they again play a crucial role in directing satellite cell function to regenerate skeletal muscle: linking the genetic control of developmental and regenerative myogenesis. Here, I review the role of the myogenic regulatory factors in developing and mature skeletal muscle, satellite cell specification and muscle regeneration.
Following their discovery in 1961, it was speculated that satellite cells were dormant myoblasts, held in reserve until required for skeletal muscle repair. Evidence for this accumulated over the ...years, until the link between satellite cells and the myoblasts that appear during muscle regeneration was finally established. Subsequently, it was demonstrated that, when grafted, satellite cells could also self-renew, conferring on them the coveted status of 'stem cell'. The emergence of other cell types with myogenic potential, however, questioned the precise role of satellite cells. Here, we review recent recombination-based studies that have furthered our understanding of satellite cell biology. The clear consensus is that skeletal muscle does not regenerate without satellite cells, confirming their pivotal and non-redundant role.
Skeletal muscle is an accessible adult stem-cell model in which differentiated myofibres are maintained and repaired by a self-renewing stem-cell compartment. These resident stem cells, which are ...known as satellite cells, lie on the surface of the muscle fibre, between the plasmalemma and overlying basal lamina. Although they are normally mitotically quiescent in adult muscle, satellite cells can be activated when needed to generate myoblasts, which eventually differentiate to provide new myonuclei for the homeostasis, hypertrophy and repair of muscle fibres, or fuse together to form new myofibres for regeneration. Satellite cells also self-renew in order to maintain a viable stem-cell pool that is able to respond to repeated demand. The study of the control of self-renewal has led to the idea that the satellite-cell pool might be heterogeneous: that is it might contain both self-renewing satellite `stem' cells and myogenic precursors with limited replicative potential in the same anatomical location. The regulatory circuits that control satellite-cell self-renewal are beginning to be deciphered, with Pax7, and Notch and Wnt signalling being clearly implicated. This Commentary seeks to integrate these interesting new findings into the wider context of satellite-cell biology, and to highlight some of the many outstanding questions.
Biophysical/biochemical cues from the environment contribute to regulation of the regenerative capacity of resident skeletal muscle stem cells called satellites cells. This can be observed in vitro, ...where muscle cell behaviour is influenced by the particular culture substrates and whether culture is performed in a 2D or 3D environment, with changes including morphology, nuclear shape and cytoskeletal organization. To create a 3D skeletal muscle model we compared collagen I, Fibrin or PEG-Fibrinogen with different sources of murine and human myogenic cells. To generate tension in the 3D scaffold, biomaterials were polymerised between two flexible silicone posts to mimic tendons. This 3D culture system has multiple advantages including being simple, fast to set up and inexpensive, so providing an accessible tool to investigate myogenesis in a 3D environment. Immortalised human and murine myoblast lines, and primary murine satellite cells showed varying degrees of myogenic differentiation when cultured in these biomaterials, with C2 myoblasts in particular forming large multinucleated myotubes in collagen I or Fibrin. However, murine satellite cells retained in their niche on a muscle fibre and embedded in 3D collagen I or Fibrin gels generated aligned, multinucleated and contractile myotubes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Growth and maintenance of skeletal muscle fibres depend on coordinated activation and return to quiescence of resident muscle stem cells (MuSCs). The transcription factor Myogenin (Myog) regulates ...myocyte fusion during development, but its role in adult myogenesis remains unclear. In contrast to mice,
zebrafish are viable, but have hypotrophic muscles. By isolating adult myofibres with associated MuSCs, we found that
myofibres have severely reduced nuclear number, but increased myonuclear domain size. Expression of fusogenic genes is decreased, Pax7 upregulated, MuSCs are fivefold more numerous and mis-positioned throughout the length of
myofibres instead of localising at myofibre ends as in wild-type. Loss of Myog dysregulates mTORC1 signalling, resulting in an 'alerted' state of MuSCs, which display precocious activation and faster cell cycle entry ex vivo, concomitant with
upregulation. Thus, beyond controlling myocyte fusion, Myog influences the MuSC:niche relationship, demonstrating a multi-level contribution to muscle homeostasis throughout life.
A central question in stem cell biology is the relationship between stem cells and their niche. Although previous reports have uncovered how signaling molecules released by niche cells support stem ...cell function, the role of the extra-cellular matrix (ECM) within the niche is unclear. Here, we show that upon activation, skeletal muscle stem cells (satellite cells) induce local remodeling of the ECM and the deposition of laminin-α1 and laminin-α5 into the basal lamina of the satellite cell niche. Genetic ablation of laminin-α1, disruption of integrin-α6 signaling or blocking matrix metalloproteinase activity impairs satellite cell expansion and self-renewal. Collectively, our findings establish that remodeling of the ECM is an integral process of stem cell activity to support propagation and self-renewal, and may explain the effect laminin-α1-containing supports have on embryonic and adult stem cells, as well as the regenerative activity of exogenous laminin-111 therapy.
Each skeletal muscle acquires its unique size before birth, when terminally differentiating myocytes fuse to form a defined number of multinucleated myofibres. Although mice in which the ...transcription factor Myogenin is mutated lack most myogenesis and die perinatally, a specific cell biological role for Myogenin has remained elusive. Here we report that loss of function of zebrafish myog prevents formation of almost all multinucleated muscle fibres. A second, Myogenin-independent, fusion pathway in the deep myotome requires Hedgehog signalling. Lack of Myogenin does not prevent terminal differentiation; the smaller myotome has a normal number of myocytes forming more mononuclear, thin, albeit functional, fast muscle fibres. Mechanistically, Myogenin binds to the myomaker promoter and is required for expression of myomaker and other genes essential for myocyte fusion. Adult myog mutants display reduced muscle mass, decreased fibre size and nucleation. Adult-derived myog mutant myocytes show persistent defective fusion ex vivo. Myogenin is therefore essential for muscle homeostasis, regulating myocyte fusion to determine both muscle fibre number and size.
Facioscapulohumeral muscular dystrophy (FSHD) is characterised by progressive skeletal muscle weakness and wasting. FSHD is linked to epigenetic derepression of the subtelomeric D4Z4 macrosatellite ...at chromosome 4q35. Epigenetic derepression permits the distal‐most D4Z4 unit to transcribe DUX4, with transcripts stabilised by splicing to a poly(A) signal on permissive 4qA haplotypes. The pioneer transcription factor DUX4 activates target genes that are proposed to drive FSHD pathology. While this toxic gain‐of‐function model is a satisfying “bottom‐up” genotype‐to‐phenotype link, DUX4 is rarely detectable in muscle and DUX4 target gene expression is inconsistent in patients. A reliable biomarker for FSHD is suppression of a target gene score of PAX7, a master regulator of myogenesis. However, it is unclear how this “top‐down” finding links to genomic changes that characterise FSHD and to DUX4. Here, we explore the roles and interactions of DUX4 and PAX7 in FSHD pathology and how the relationship between these two transcription factors deepens understanding via the immune system and muscle regeneration. Considering how FSHD pathomechanisms are represented by “DUX4opathy” models has implications for developing therapies and current clinical trials.
In this review CRS Banerji and PS Zammit discuss the relationship between transcription factors DUX4 and PAX7 in the pathology of facioscapulohumeral muscular dystrophy.
The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained ...YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.
•YAP1-driven ERMS can originate in activated but not quiescent satellite cells•YAP1 locks the ERMS myoblast phenotype by globally reducing MYOD1 and MEF2 activity•YAP1-ERMS activity signature classifies ERMS cases according to stage and severity•YAP1 inhibition is a promising strategy for differentiation therapy of ERMS
Tremblay et al. identify Yap1 hyperactivity as a major molecular cause of embryonal rhabdomyosarcoma (ERMS) and generate a mouse ERMS model with high penetrance and short latency. Yap1 increases the expression of pro-proliferative and oncogenic genes while interfering with the pro-differentiation program.
Neuromuscular disorders are a heterogeneous group of acquired or hereditary conditions that affect striated muscle function. The resulting decrease in muscle strength and motility irreversibly ...impacts quality of life. In addition to directly affecting skeletal muscle, pathogenesis can also arise from dysfunctional crosstalk between nerves and muscles, and may include cardiac impairment. Muscular weakness is often progressive and paralleled by continuous decline in the ability of skeletal muscle to functionally adapt and regenerate. Normally, the skeletal muscle resident stem cells, named satellite cells, ensure tissue homeostasis by providing myoblasts for growth, maintenance, repair and regeneration. We recently defined 'Satellite Cell-opathies' as those inherited neuromuscular conditions presenting satellite cell dysfunction in muscular dystrophies and myopathies (doi:10.1016/j.yexcr.2021.112906). Here, we expand the portfolio of Satellite Cell-opathies by evaluating the potential impairment of satellite cell function across all 16 categories of neuromuscular disorders, including those with mainly neurogenic and cardiac involvement. We explore the expression dynamics of myopathogenes, genes whose mutation leads to skeletal muscle pathogenesis, using transcriptomic analysis. This revealed that 45% of myopathogenes are differentially expressed during early satellite cell activation (0 - 5 hours). Of these 271 myopathogenes, 83 respond to Pax7, a master regulator of satellite cells. Our analysis suggests possible perturbation of satellite cell function in many neuromuscular disorders across all categories, including those where skeletal muscle pathology is not predominant. This characterisation further aids understanding of pathomechanisms and informs on development of prognostic and diagnostic tools, and ultimately, new therapeutics.
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