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Developmental Biology May 2010Cell-cell fusion is a crucial and highly regulated event in the genesis of both form and function of many tissues. One particular type of cell fusion, myoblast fusion,... (Review)
Review
Cell-cell fusion is a crucial and highly regulated event in the genesis of both form and function of many tissues. One particular type of cell fusion, myoblast fusion, is a key cellular process that shapes the formation and repair of muscle. Despite its importance for human health, the mechanisms underlying this process are still not well understood. The purpose of this review is to highlight the recent literature pertaining to myoblast fusion and to focus on a comparison of these studies across several model systems, particularly the fly, zebrafish and mouse. Advances in technical analysis and imaging have allowed identification of new fusion genes and propelled further characterization of previously identified genes in each of these systems. Among the cellular steps identified as critical for myoblast fusion are migration, recognition, adhesion, membrane alignment and membrane pore formation and resolution. Importantly, striking new evidence indicates that orthologous genes govern several of these steps across these species. Taken together, comparisons across three model systems are illuminating a once elusive process, providing exciting new insights and a useful framework of genes and mechanisms.
Topics: Animals; Cell Fusion; Drosophila; Humans; Mice; Muscle Development; Myoblasts
PubMed: 19932206
DOI: 10.1016/j.ydbio.2009.10.024 -
Current Topics in Developmental Biology 2011Myoblast fusion contributes to muscle growth in development and during regeneration of mature muscle. Myoblasts fuse to each other as well as to multinucleate myotubes... (Review)
Review
Myoblast fusion contributes to muscle growth in development and during regeneration of mature muscle. Myoblasts fuse to each other as well as to multinucleate myotubes to enlarge the myofiber. The molecular mechanisms of myoblast fusion are incompletely understood. Adhesion, apposition, and membrane fusion are accompanied by cytoskeletal rearrangements. The ferlin family of proteins is implicated in human muscle disease and has been implicated in fusion events in muscle, including myoblast fusion, vesicle trafficking and membrane repair. Dysferlin was the first mammalian ferlin identified and it is now known that there are six different ferlins. Loss-of-function mutations in the dysferlin gene lead to limb girdle muscular dystrophy and the milder disorder Miyoshi Myopathy. Dysferlin is a membrane-associated protein that has been implicated in resealing disruptions in the muscle plasma membrane. Newer data supports a broader role for dysferlin in intracellular vesicular movement, a process also important for resealing. Myoferlin is highly expressed in myoblasts that undergoing fusion, and the absence of myoferlin leads to impaired myoblast fusion. Myoferlin also regulates intracellular trafficking events, including endocytic recycling, a process where internalized vesicles are returned to the plasma membrane. The trafficking role of ferlin proteins is reviewed herein with a specific focus as to how this machinery alters myogenesis and muscle growth.
Topics: Animals; Humans; Muscle Development; Muscle Proteins; Muscle, Skeletal; Myoblasts; Wound Healing
PubMed: 21621072
DOI: 10.1016/B978-0-12-385940-2.00008-5 -
Molecular Medicine Reports Apr 2018Lactoferrin (Lf) is a multifunctional glycoprotein, which promotes the proliferation of murine C2C12 myoblasts. In the present study, it was investigated how Lf promotes...
Lactoferrin (Lf) is a multifunctional glycoprotein, which promotes the proliferation of murine C2C12 myoblasts. In the present study, it was investigated how Lf promotes myoblast proliferation and whether Lf promotes myoblast differentiation or induces myotube hypertrophy. Lf promoted the proliferation of myoblasts in a dose‑dependent manner. Myoblast proliferation increased on day 3 when myoblasts were cultured in the presence of Lf for three days and also when myoblasts were cultured in the presence of Lf for the first day and in the absence of Lf for the subsequent two days. In addition, Lf induced the phosphorylation of extracellular signal‑regulated kinase (ERK)1/2 in myoblasts. The mitogen‑activated protein kinase kinase 1/2 inhibitor U0126 inhibited Lf‑induced ERK1/2 phosphorylation and repressed Lf‑promoted myoblast proliferation. C2C12 myoblasts, myotubes and skeletal muscle expressed low‑density lipoprotein receptor‑related protein (LRP)1 mRNA and Lf‑promoted myoblast proliferation was attenuated by an LRP1 antagonist or LRP1 gene silencing. The knockdown of LRP1 repressed Lf‑induced phosphorylation of ERK1/2. Furthermore, when myoblasts were induced to differentiate, Lf increased the expression of the myotube‑specific structural protein, myosin heavy chain (MyHC) and promoted myotube formation. Knockdown of LRP1 repressed Lf‑induced MyHC expression. Lf also increased myotube size following differentiation. These results indicate that Lf promotes myoblast proliferation and differentiation, at least partially through LRP1 and also stimulates myotube hypertrophy.
Topics: Animals; Cell Differentiation; Cell Line; Cell Proliferation; Hypertrophy; Lactoferrin; Low Density Lipoprotein Receptor-Related Protein-1; MAP Kinase Signaling System; Male; Mice; Mitogen-Activated Protein Kinase 3; Muscle Fibers, Skeletal; Myoblasts; Receptors, LDL; Tumor Suppressor Proteins
PubMed: 29436684
DOI: 10.3892/mmr.2018.8603 -
Experimental Cell Research Nov 2010The body wall musculature of a Drosophila larva is composed of an intricate pattern of 30 segmentally repeated muscle fibers in each abdominal hemisegment. Each muscle... (Review)
Review
The body wall musculature of a Drosophila larva is composed of an intricate pattern of 30 segmentally repeated muscle fibers in each abdominal hemisegment. Each muscle fiber has unique spatial and behavioral characteristics that include its location, orientation, epidermal attachment, size and pattern of innervation. Many, if not all, of these properties are dictated by founder cells, which determine the muscle pattern and seed the fusion process. Myofibers are then derived from fusion between a specific founder cell and several fusion competent myoblasts (FCMs) fusing with as few as 3-5 FCMs in the small muscles on the most ventral side of the embryo and as many as 30 FCMs in the larger muscles on the dorsal side of the embryo. The focus of the present review is the formation of the larval muscles in the developing embryo, summarizing the major issues and players in this process. We have attempted to emphasize experimentally-validated details of the mechanism of myoblast fusion and distinguish these from the theoretically possible details that have not yet been confirmed experimentally. We also direct the interested reader to other recent reviews that discuss myoblast fusion in Drosophila, each with their own perspective on the process [1-4]. With apologies, we use gene nomenclature as specified by Flybase (http://flybase.org) but provide Table 1 with alternative names and references.
Topics: Animals; Cell Fusion; Drosophila; Embryo, Nonmammalian; Muscle, Skeletal; Myoblasts
PubMed: 20580706
DOI: 10.1016/j.yexcr.2010.05.018 -
Development (Cambridge, England) Feb 2012The fusion of myoblasts into multinucleate syncytia plays a fundamental role in muscle function, as it supports the formation of extended sarcomeric arrays, or... (Review)
Review
The fusion of myoblasts into multinucleate syncytia plays a fundamental role in muscle function, as it supports the formation of extended sarcomeric arrays, or myofibrils, within a large volume of cytoplasm. Principles learned from the study of myoblast fusion not only enhance our understanding of myogenesis, but also contribute to our perspectives on membrane fusion and cell-cell fusion in a wide array of model organisms and experimental systems. Recent studies have advanced our views of the cell biological processes and crucial proteins that drive myoblast fusion. Here, we provide an overview of myoblast fusion in three model systems that have contributed much to our understanding of these events: the Drosophila embryo; developing and regenerating mouse muscle; and cultured rodent muscle cells.
Topics: Animals; Cell Adhesion; Cell Communication; Cell Differentiation; Cell Fusion; Cell Movement; Cell Surface Extensions; Cells, Cultured; Cytoskeletal Proteins; Cytoskeleton; Drosophila; Giant Cells; Membrane Fusion; Mice; Morphogenesis; Muscle, Skeletal; Myoblasts; Regeneration; Signal Transduction
PubMed: 22274696
DOI: 10.1242/dev.068353 -
Science Signaling Apr 2013Myoblast fusion is a critical process that contributes to the growth of muscle during development and to the regeneration of myofibers upon injury. Myoblasts fuse with... (Review)
Review
Myoblast fusion is a critical process that contributes to the growth of muscle during development and to the regeneration of myofibers upon injury. Myoblasts fuse with each other as well as with multinucleated myotubes to enlarge the myofiber. Initial studies demonstrated that myoblast fusion requires extracellular calcium and changes in cell membrane topography and cytoskeletal organization. More recent studies have identified several cell-surface and intracellular proteins that mediate myoblast fusion. Furthermore, emerging evidence suggests that myoblast fusion is also regulated by the activation of specific cell-signaling pathways that lead to the expression of genes whose products are essential for the fusion process and for modulating the activity of molecules that are involved in cytoskeletal rearrangement. Here, we review the roles of the major signaling pathways in mammalian myoblast fusion.
Topics: Animals; Calcium; Cell Fusion; Cell Membrane; Giant Cells; Humans; Muscle Fibers, Skeletal; Muscle Proteins; Myoblasts; Signal Transduction
PubMed: 23612709
DOI: 10.1126/scisignal.2003832 -
Stem Cell Reports Oct 2023Skeletal muscle research is transitioning toward 3D tissue engineered in vitro models reproducing muscle's native architecture and supporting measurement of...
Skeletal muscle research is transitioning toward 3D tissue engineered in vitro models reproducing muscle's native architecture and supporting measurement of functionality. Human induced pluripotent stem cells (hiPSCs) offer high yields of cells for differentiation. It has been difficult to differentiate high-quality, pure 3D muscle tissues from hiPSCs that show contractile properties comparable to primary myoblast-derived tissues. Here, we present a transgene-free method for the generation of purified, expandable myogenic progenitors (MPs) from hiPSCs grown under feeder-free conditions. We defined a protocol with optimal hydrogel and medium conditions that allowed production of highly contractile 3D tissue engineered skeletal muscles with forces similar to primary myoblast-derived tissues. Gene expression and proteomic analysis between hiPSC-derived and primary myoblast-derived 3D tissues revealed a similar expression profile of proteins involved in myogenic differentiation and sarcomere function. The protocol should be generally applicable for the study of personalized human skeletal muscle tissue in health and disease.
Topics: Humans; Induced Pluripotent Stem Cells; Proteomics; Cells, Cultured; Muscle, Skeletal; Tissue Engineering; Myoblasts; Cell Differentiation
PubMed: 37774701
DOI: 10.1016/j.stemcr.2023.08.014 -
Seminars in Cell & Developmental Biology Dec 2017The study of Drosophila muscle development dates back to the middle of the last century. Since that time, Drosophila has proved to be an ideal system for studying muscle... (Review)
Review
The study of Drosophila muscle development dates back to the middle of the last century. Since that time, Drosophila has proved to be an ideal system for studying muscle development, differentiation, function, and disease. As in humans, Drosophila muscle forms via a series of conserved steps, starting with muscle specification, myoblast fusion, attachment to tendon cells, interactions with motorneurons, and sarcomere and myofibril formation. The genes and mechanisms required for these processes share striking similarities to those found in humans. The highly tractable genetic system and imaging approaches available in Drosophila allow for an efficient interrogation of muscle biology and for application of what we learn to other systems. In this article, we review our current understanding of muscle development in Drosophila, with a focus on myoblast fusion, the process responsible for the generation of syncytial muscle cells. We also compare and contrast those genes required for fusion in Drosophila and vertebrates.
Topics: Animals; Cell Differentiation; Cell Fusion; Gene Expression Regulation, Developmental; Giant Cells; Humans; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts
PubMed: 29101004
DOI: 10.1016/j.semcdb.2017.10.033 -
Current Opinion in Genetics &... Jun 2015The development and regeneration of skeletal muscle require the fusion of mononucleated muscle cells to form multinucleated, contractile muscle fibers. Studies using a... (Review)
Review
The development and regeneration of skeletal muscle require the fusion of mononucleated muscle cells to form multinucleated, contractile muscle fibers. Studies using a simple genetic model, Drosophila melanogaster, have discovered many evolutionarily conserved fusion-promoting factors in vivo. Recent work in zebrafish and mouse also identified several vertebrate-specific factors required for myoblast fusion. Here, we integrate progress in multiple in vivo systems and highlight conceptual advance in understanding how muscle cell membranes are brought together for fusion. We focus on the molecular machinery at the fusogenic synapse and present a three-step model to describe the molecular and cellular events leading to fusion pore formation.
Topics: Animals; Cell Fusion; Cell Membrane; Drosophila; Mice; Models, Animal; Models, Biological; Muscle, Skeletal; Myoblasts, Skeletal; Regeneration; Zebrafish
PubMed: 25989064
DOI: 10.1016/j.gde.2015.03.006 -
Cells Nov 2022Myoblast differentiation is a complex process whereby the mononuclear muscle precursor cells myoblasts express skeletal-muscle-specific genes and fuse with each other to...
Myoblast differentiation is a complex process whereby the mononuclear muscle precursor cells myoblasts express skeletal-muscle-specific genes and fuse with each other to form multinucleated myotubes. The objective of this study was to identify potentially novel mechanisms that mediate myoblast differentiation. We first compared transcriptomes in C2C12 myoblasts before and 6 days after induction of myogenic differentiation by RNA-seq. This analysis identified 11,046 differentially expressed genes, of which 5615 and 5431 genes were upregulated and downregulated, respectively, from before differentiation to differentiation. Functional enrichment analyses revealed that the upregulated genes were associated with skeletal muscle contraction, autophagy, and sarcomeres while the downregulated genes were associated with ribonucleoprotein complex biogenesis, mRNA processing, ribosomes, and other biological processes or cellular components. Western blot analyses showed an increased conversion of LC3-I to LC3-II protein during myoblast differentiation, further demonstrating the upregulation of autophagy during myoblast differentiation. Blocking the autophagic flux in C2C12 cells with chloroquine inhibited the expression of skeletal-muscle-specific genes and the formation of myotubes, confirming a positive role for autophagy in myoblast differentiation and fusion.
Topics: Up-Regulation; Muscle Development; Myoblasts; Autophagy; RNA
PubMed: 36428978
DOI: 10.3390/cells11223549