Lectura 3.

- Tejido Muscular
Histology – A Text and Atlas.- Michael H. Ross, Wojciech Pawlina. Sixth Edition. Pag. 325-327

Development, Repair, Healing, and Renewal

Development of myogenic stem cell linage depends on expression of various myogenic regulatory actors.
Myoblasts are derived from a self-renewing population of multipotential myogenic stem cells that originate in the
embryo from unsegmented paraxial mesoderm (cranial muscle progenitors) or segmented mesoderm of somites
(epaxial and hypaxial muscle progenitors). Early in embryonic development, these cells express MyoD
transcription factor, which, along with other myogenic regulatory factors (MRFs), plays a key role in activation
of muscle-specific gene expressions and differentiation of all skeletal muscle lineages. A balancing
effect on skeletal-muscle development is achieved by the expression of negative regulatory myostatin gene, which
leads to synthesis of myostatin, a 26-kilodalton protein belonging to the bone morphogenetic protein/transforming
growth factor-_ (BMP/TGF-_) protein superfamily. Myostatin exerts an inhibitory effect on muscle growth and
differentiation. It is thought that MyoD preferentially upregulates myostatin gene expression and controls
myogenesis during not only the embryonic and fetal periods but also postnatal
stages of the development. The hypermuscular phenotypes observed on inactivation of the myostatin gene in
animals and humans have confirmed the role of myostatin as a negative regulator of skeletal-muscle
development. Experimental studies have demonstrated that muscle mass increases through myostatin
inhibition, and the myostatin signaling pathway may be a potent therapeutic intervention point in the
treatment of muscle-wasting diseases, such as muscular dystrophy, amyotrophic lateral sclerosis (ALS),
AIDS, and cancer. Pharmacologic manipulation of myostatin expression could also lead to the development
of new therapeutic approaches in a variety of musculoskeletal pathologies.
Skeletal muscle progenitors differentiate into early and late myoblasts.
Developing muscle contains two types of myoblasts:

• Early myoblasts are responsible for the formation of primary myotubes, chainlike structures that extend
between tendons of the developing muscle. Primary myotubes are formed by nearly synchronous fusion of early
myoblasts. Myotubes undergo further differentiation into mature skeletal muscle fibers. Primary myotubes
observed in the light microscope exhibit a chain of multiple central nuclei surrounded by myofilaments.

• Late myoblasts give rise to secondary myotubes,

which are formed in the innervated zone of developing
muscle where the myotubes have direct contact with
nerve terminals. Secondary myotubes continue to be
formed by sequential fusion of myoblasts into the
already-formed secondary myotubes at random positions
along their length. Secondary myotubes are characterized
by a smaller diameter, more widely spaced
nuclei, and an increased number of myofilaments
(Fig. 11.13). In the mature multinucleated muscle fiber,
the nuclei are all in the peripheral sarcoplasm, just
inside the plasma membrane.
Some nuclei that appear to belong to the skeletal muscle
fiber are nuclei of satellite cells. Satellite cells are interposed
between the plasma membrane of the muscle fiber and its
external lamina. They are small cells with scant cytoplasm.
The cytoplasm typically blends in with the muscle cell
sarcoplasm when viewed in the light microscope, thus making
them difficult to identify. Each satellite cell has a single nucleus with a chromatin network
denser and coarser than that of muscle cell nuclei. Satellite cells
are responsible for the skeletal muscle’s ability to regenerate,
but their regenerative capacity is limited. These myogenic precursors of muscle cells are normally quiescent and
do not express myogenic regulatory factors. However, after injury of muscle tissue, some satellite cells become
activated, reenter the cell cycle, and begin to express MRFs. They proliferate and give rise to new myoblasts. As
long as the external lamina remains intact, the myoblasts fuse within the external lamina to
form myotubes, which then mature into a new fiber. In contrast, if the external lamina is disrupted, fibroblasts
repair the injured site, with subsequent scar tissue formation. Muscular dystrophies are characterized by
progressive degeneration of skeletal muscle fibers, which places a constant demand on the satellite cells to
replace the degenerated fibers. Ultimately, the satellite cell pool is exhausted. New experimental data
indicate that, during this process, additional myogenic cells are recruited from the bone marrow and
supplement the available satellite cells. The rate of degeneration exceeds the rate of regeneration, however,
resulting in loss of muscle function. A future treatment strategy for muscular dystrophies may include the
transplantation of satellite cells or their myogenic bone marrow counterparts into damaged muscle.