The cardiac muscle pumps blood through the body and is under involuntary control. Smooth muscle tissue contraction is responsible for involuntary movements in the internal organs.
It forms the contractile component of the digestive, urinary, and reproductive systems as well as the airways and blood vessels. Each cell is spindle shaped with a single nucleus and no visible striations Figure 4. Watch this video to learn more about muscle tissue. In looking through a microscope how could you distinguish skeletal muscle tissue from smooth muscle? The three types of muscle cells are skeletal, cardiac, and smooth. Their morphologies match their specific functions in the body.
Skeletal muscle is voluntary and responds to conscious stimuli. The cells are striated and multinucleated appearing as long, unbranched cylinders. Cardiac muscle is involuntary and found only in the heart.
Each cell is striated with a single nucleus and they attach to one another to form long fibers. Cells are attached to one another at intercalated disks. The cells are interconnected physically and electrochemically to act as a syncytium.
Cardiac muscle cells contract autonomously and involuntarily. Smooth muscle is involuntary. Each cell is a spindle-shaped fiber and contains a single nucleus.
No striations are evident because the actin and myosin filaments do not align in the cytoplasm. You are watching cells in a dish spontaneously contract. They are all contracting at different rates, some fast, some slow. After a while, several cells link up and they begin contracting in synchrony. Defects in myofiber growth are intrinsic to muscle cells since cultured muscle cells lacking NFATC2 form small myotubes with few nuclei.
Muscle growth results from an ordered sequence of events. Withdrawal of mitogens in vitro causes myoblasts to exit the cell cycle and activate the expression of differentiation specific genes. Subsequently, myoblasts migrate toward one another, elongate, align, and through cell—cell interactions fuse together to form a multinucleated cell. Multiple proteins are required for migration and fusion of myoblasts such as integrins and other cell adhesion molecules, metalloproteases, and phospholipases Knudsen In addition, increases in intracellular calcium Constantin et al.
Once myotubes form, additional myoblasts fuse with the myotube, and the myotube grows in size. Postnatal muscle growth in vivo is also characterized by myoblast fusion with myofibers, leading to an increase in myonuclear number. Numerous studies indicate that myoblasts are critical for muscle growth in vivo. When the proliferative capacity of myoblasts is attenuated, increases in myonuclear number and myofiber size are blocked in growing rats Darr and Schultz ; Rosenblatt and Parry ; Mozdziak et al.
Additionally, the lack of myoblast growth factors such as leukemia inhibitory factor Kurek et al. Thus, numerous molecules contribute to proper muscle cell size.
The decrease in the number of nuclei is correlated with a decrease in myotube size, implicating an NFATC2-dependent pathway in the control of myotube size. Thus, the downstream targets of NFATC2 allow the fusion of differentiated muscle cells with newly formed myotubes and the subsequent growth of the myotube.
Based on our results, we present the model outlined in Fig. Increases in intracellular calcium lead to the activation of calcineurin. NFATC2 may either directly or indirectly regulate gene transcription of a cell surface protein pathway 1 that mediates cell—cell interaction or cell fusion between mononucleated muscle cells and newly formed myotubes. Evidence exists for cell surface proteins that mediate the fusion of myoblasts with myotubes.
The integrin very late antigen 4 on multinucleated muscle cells and its counterreceptor vascular cell adhesion molecule 1 on myoblasts are thought to mediate myoblast fusion with myofibers during development Rosen et al.
In addition, glycoproteins may mediate myoblast—myotube interactions to allow fusion and muscle growth, since wheat germ agglutinin can block myoblast fusion with myotubes and decrease myotube size Muroya et al. Alternatively, NFATC2 could either directly or indirectly regulate gene transcription of a secreted protein pathway 2 that recruits differentiated mononucleated myoblasts to fuse with adjacent myotubes.
Secreted factors apparently can regulate the fusion of cells with myotubes. Fibroblasts cocultured with young or old myotubes can acquire myogenic characteristics and fuse with myotubes Breton et al. Though not shown, both pathway 1 and 2 could also mediate myotube—myotube fusion.
Specific molecules downstream from NFATC2 that contribute to muscle growth, though not examined in this study, are currently being investigated. Only myoblast fusion is represented in the model. NFATC2 may regulate a cell surface protein pathway 1 that mediates cell—cell interaction or cell fusion between differentiated muscle cells and newly formed myofibers. Alternatively, NFATC2 could regulate gene transcription of a secreted protein pathway 2 that recruits differentiated muscle cells to fuse with adjacent myofibers.
Myotube—myotube fusion has been suggested to occur during regeneration Robertson et al. Several lines of evidence implicate multinucleated cells as controlling the site and extent of myoblast fusion. During the development of mammalian skeletal muscle, primary myofibers form initially and are followed by the formation of secondary myofibers. Primary myofibers control the site of secondary myofiber assembly, since secondary myofibers form only at the site of innervation on the primary myofiber, independently of the nerve Duxson et al.
In addition, the primary myofiber seems to restrict the fusion of secondary myoblasts, whereas the secondary myofiber seems to recruit fusion, since secondary myoblasts fuse primarily with the forming secondary myofiber Harris et al. This specificity of fusion shares analogy with Drosophila muscle development in which founder myoblasts express dumbfounded, an attractant for myoblast fusion, and recruit fusion-competent myoblasts to fuse with founder myoblasts and not with other myoblasts Ruiz-Gomez et al.
Further suggesting that myofibers can control the location of myoblast fusion, myofibers elongate by fusion of myoblasts at their ends during mammalian postnatal growth Williams and Goldspink ; Zhang and McLennan The mechanisms by which myofibers regulate the fusion of myoblasts are unknown but may involve expression of proteins such as those mentioned above.
This control of fusion by multinucleated muscle cells is likely one mechanism by which the size of muscle cells is regulated. Calcineurin has been shown to be involved in skeletal muscle hypertrophy Musaro et al.
The inability of NFATC2 overexpression to induce an increase in myotube size and nuclear number in wild-type myotubes suggests that NFATC2 is not involved in skeletal muscle hypertrophy. Several possibilities exist to explain this lack of effect on growth of wild-type myotubes. This hypothesis is supported by the fact that NFATC2 cannot be activated by a calcium ionophore in mature myotubes Abbott et al.
These pathways could involve the activation of additional transcription factors necessary for forming a transcriptional complex with NFATC2. Thus, wild-type myotubes already may be at their maximal cell size and no further increases are possible even in the presence of the recombinant NFATC2. In summary, we demonstrate that the calcium-regulated transcription factor NFATC2 regulates muscle growth. These data implicate an NFAT-dependent pathway in newly formed myotubes that controls further cell fusion in a mechanism that is distinct from the initial formation of multinucleated muscle cells.
Myoblast fusion with multinucleated cells is central to proper muscle development but is also clinically relevant. Enhancing myoblast fusion with multinucleated cells has potential therapeutic value by improving the fusion of endogenous myoblasts in the treatment of muscle injuries or muscle atrophy or by enhancing the fusion of exogenous transplanted myoblasts in gene therapy protocols Blau and Springer Both myotonic dystrophy Farkas-Bargeton et al.
Further studies will be directed towards identifying genes regulated by NFATC2 and their regulation of the fusion of differentiated muscle cells with multinucleated muscle cells. We thank Dr. National Center for Biotechnology Information , U. Journal List J Cell Biol v. J Cell Biol. Valerie Horsley , a Bret B. Pavlath a. Bret B. Grace K. Author information Article notes Copyright and License information Disclaimer. Rollins Research Bldg. Pavlath: ude. This article has been cited by other articles in PMC.
Abstract The nuclear factor of activated T cells NFAT family of transcription factors regulates the development and differentiation of several tissue types.
Introduction Calcium is an important regulator of skeletal muscle physiology. Collection of Muscles and Morphometric Measurements Tibialis anterior TA , soleus, and masseter muscles were collected using standardized dissection methods, embedded in TBS tissue freezing medium Fisher Scientific , and frozen in isopentane cooled in liquid nitrogen.
Immunohistochemistry To analyze particular fiber types, cross sections of soleus muscles were stained with antibodies against type 1 BA-D5 Schiaffino et al.
Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Discussion We have shown previously that individual NFAT proteins translocate to the nucleus of muscle cells at specific stages of myogenesis Abbott et al.
Figure 7. Acknowledgments We thank Dr. References Abbott K. Activation and cellular localization of the cyclosporine A-sensitive transcription factor NF-AT in skeletal muscle cells. Successive expression and activation of NFAT family members during thymocyte differentiation. Myonuclear domains in muscle adaptation and disease. Muscle Nerve. Myogenin expression, cell cycle withdrawal, and phenotypic differentiation are temporally separable events that precede cell fusion upon myogenesis.
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IN many cell types differentiation is closely associated with the end of DNA synthesis. The differentiation of muscle cells is a typical example. The formation of muscle fibres takes place by the successive fusion of mononucleated myoblasts into ribbon like cells, containing as many as several hundred nuclei.
After fusion, the nuclei within the fibres do not synthesize DNA, do not undergo mitosis 1—4 and apparently are also restricted in RNA synthesis 5,6. Konigsberg, I. Stockdale, F. Yaffe, D. Betz, E. Dulbecco, R. US Nat. Weil, R.
Winocour, E. Google Scholar. Gershon, D.
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