Download Development of Vertebrate Skeletal Muscle Skeletal muscle is

AMER. ZOOL., 18:101-111 (1978)..
Development of Vertebrate Skeletal Muscle
E. RAWORTH ALLEN
Department of Anatomy, Louisiana State University Medical Center, New Orleans,
Louisiana 70119
SYNOPSIS. An investigation of developing skeletal muscle necessitates the study of three
categories; the derivation of muscle cells or fibers, myofilament synthesis and interactions,
assembly of myofilaments into functional sarcomeres of striated myofibrils. With few
exceptions, skeletal muscle cells are of mesodermal origin, and consist of rounded
mononucleated cells which elongate and fuse with one another to become myotubes.
Within the sarcoplasm, myofibrillar proteins are synthesized and grouped into interacting
thick and thin filaments. Crude, non-striated myofibrils result from linear arrangements of
thick and'thin filaments which are horizontally aligned by the invaginating sarcotubular
system. After Z-lines form, providing attachment sites for thin filaments, a typical banding
pattern follows. The newly formed Z-lines pull apart, followed by the attached thin
filaments, and repeating "relaxed" sarcomeres are the resulting striated myofibrillar
pattern.
others, and attempt to put some of the
conflicting studies together into a concise
Skeletal muscle is composed of story.
specialized, multinucleated, cylindrical
Before beginning the discussion of decells or fibers which display alternating veloping skeletal muscle, a brief review of
light and dark bands. The striated or the structure and composition of mature
banded appearance is created by repeating myofibrils is necessary. In a light microsubunits called sarcomeres, demonstrated graph of muscle (Fig. 1), longitudinal striajust thirty-five years ago to be composed tions are visible due to the parallel arof small filaments, or myofilaments (Hall et rangement of myofibrils. Each fibril is
al, 1946).
composed of periodic sarcomeres which
When discussing the development of are in turn composed of myofilaments.
skeletal muscle, one must give major con- These sarcomeres, in lateral register with
cern to three categories: (1) the muscle one another, create the transverse striacell—where it is embryologically derived tions or banding patterns which are clearly
and how are its developmental stages seen in electron micrographs (Fig. 2) of
characterized, (2) the myofilaments—how skeletal muscle. The distance from one
are they synthesized and when do they dense Z-line to another includes one sarappear during development, and (3) the comere. The darker band found in the
myofibril—how do the myofilaments fit center of the sarcomere is the A band, with
together to form a functional sarcomere. less dense I bands on either side. The H
Excellent literature reviews concerning zone is the light area in the center of the A
different aspects of these three questions band, bissected by a dense M-line. The
are readily available (Boyd, 1960; Holtzer, longitudinally oriented sarcoplasmic re1961; Fischman, 1972; Allen, 1973a). In ticulum and its relationship to the transthis symposium, I will discuss briefly some verse T-tubules is clearly indicated. Elonaspects of these investigations as well as gate mitochondria are also apparent in this
fully differentiated skeletal muscle from
I acknowledge the technical assistance of Elizabeth the nine-banded armadillo (Ruby and
Underwood in various aspects of the original investi- Allen, 1976). Two distinct classes of myofiagations. Mr. Garbis Kerimian provided photographic ments (thick and thin) have been isolated
assistance and Dr. John Ruby critically read portions and characterized both from adult skeletal
of the manuscript. The original work was supported
muscle and from purified preparations of
in part by Muscular Dystrophy Association, U.S.A.
INTRODUCTION
101
102
E. RAWORTH ALLEN
_?••*-
FIG. 1. Photomicrograph of mammalian skeletal
muscle provided by Dr. James May, 1977. Note
longitudinal striations (myofibrils) and transverse
striations (sarcomeres). x 1360.
myosin and actin (Huxley, 1961; Hanson
and Lowy, 1963). The A band is composed
of thick myosin filaments approximately
1.5/Ltm long and 11-12 nm in width (Figs.
2,4). Thick filaments are continuous from
one end of the A band to the other. The
M-line is apparently purely structural in
FIG. 2. Electron micrograph of skeletal muscle from
the tongue musculature of the nine-banded armadillo. One sarcomere is labelled. Note A bands (A),
I bands (I), Z-lines (Z), H zone (H), and the M line
nature and functions to help preserve the
integrity of the thick filaments (Kundrat
and Pepe, 1971). Thin filaments approximately 6 nm in width consist of two helically wound strands of 5 nm actin
monomer subunits. Filament lengths measure approximately ljam (Pepe and Huxley, 1964). Unlike the thick filaments,
which are thought to contain myosin
molecules, the thin, actin filaments are
known to have other minor but necessary
contractile proteins associated with them.
Tropomyosin is in the form of a strand,
lying in the groove created by the tightly
bound actin filaments (Ebashi and Endo,
1968). Troponin is a complex structure
distributed at 38.5-4.0 nm intervals along
the thin filament (Ebashi and Endo, 1968).
The Z-line contains a dense proteinaceous
material that affords attachment of thin
filaments, either by "Z" filaments" (Knappeis and Carlsen, 1962) or by an interwining mechanism (Kelly, 1969). a actinin is
(arrow). The sarcoplasmic reticulum (s) and the
transverse T tubules (arrowhead) are both present,
x 25,650.
SKELETAL MUSCLE DEVELOPMENT
thought to be contained within the dense
Z-line (Stromer et al., 1969), whereas /3
actinin is found associated with the thin
filament itself (Maruyama, 1965).
THE MUSCLE CELL
With few exceptions (See Boyd, 1960)
skeletal muscle is of mesodermal origin.
Narayanan and Narayanan (unpublished
observations), however, recently described
a striated muscle of the iris in birds that is
innervated by visceral efferent nerves and
derived from neural ectoderm. In contrast
to smooth muscle fibers found in the
mammalian iris, striated fibers are essential
in birds because of the necessity of quick
light adaptability during flight. Other
skeletal muscle found in the head includes
two embryologically different groups. One
group is from visceral (branchial) arch
mesoderm and gives rise to masticatory,
laryngeal, pharyngeal, and mimetic muscles. The other group is from myotomes
(found within somites) and gives rise to the
extraocular and tongue musculature. According to Huber, (1931), certain muscles
of the shoulder also belong to this latter
group. The remainder of the trunk musculature is derived from somites and lateral
plate mesoderm (Strauss and Rawles,
1953) or exclusively somites (Detwiler,
1955; Theiler, 1957; Liedke, 1958). Limb
musculature is derived from local condensations of lateral plate (somatopleuric)
mesoderm. (See review by Fischman,
1972).
Undifferentiated mesenchymal cells, destined to become muscle, are not easily
identified from the other embryonic
mesenchymal cells. In general they are of a
round shape containing an ovoid nucleus
with one or two prominant nucleoli. They
also contain numerous free ribosomes and
short polyribosomes, and usually a small
amount of poorly developed rough surfaced endoplasmic reticulum. The cells
elongate and become bipolar, in contrast to
triangular or polygonal shaped mesenchymal cells that will not become muscle.
Capers (1960) and Cooper and Konigsberg
(1961) observed mononucleated muscle
cells fusing to become multinucleated
103
myotubes in culture, recording the act in
the time lapse cinematography. Muscle
cells are readily identified in the fusion
process in vivo when we are utilizing 3-4
day chick embryos (Stage 20) in our
laboratory. The method by which
myotubes become multinucleated has been
proposed by Holtzer et al., (1957) to be by
the fusion of mononucleated myoblasts
with other myoblasts or myotubes and not
by mitotic, amitotic or some other means
(see Fischman, 1972). A confusing terminology for the developing muscle cell
has appeared in the literature since Godlewski first introduced the term "myoblast"
in 1902 (see Boyd, 1960). Holtzer and
colleagues (see Holtzer, 1970) proposed a
widely accepted nomenclature. They term
any postmitotic, mononucleated cell, capable of both fusion and the synthesis of
contractile proteins a "myoblast." They
further state that the myoblasts are immediate descendants of "presumptive
myoblasts" which cannot fuse nor synthesize myosin.
Although some evidence has been presented for myofibrillar protein synthesis in
mononucleated cells (Holtzer et al., 1957;
Przybylski and Blumberg, 1966; Fambrough and Rash, 1972), it appears that
myotubes are the location of the bulk of
myofibrillar protein synthesis and assembly of myofilaments (Fischman, 1972).
With the initial onset of myosin synthesis,
large polyribosomes containing 50-60 ribosomes in a chain and shown to be actively
synthesizing myosin (Allen and Terrence,
1968) are found in the sarcoplasm of
myotubes. There is also an increase in
length and number of mitochondria observed in the myotube, both in electron
microscopy of in vivo studies (Allen and
Pepe, 1965) and from enzyme histochemical data of in vitro investigations (Cooper
and Konigsberg, 1961). Long polyribosomes, elongated mitochondria and early
stages of myofibrillogenesis are seen in
Figure 3. Suggestions of cell fusion are also
indicated in these embryonic chick cells.
The surface of the myotube is coated at an
early developmental stage with a
glycocalyx called a basal lamina. Okazaki
and Holtzer (1966) and Fischman (1970)
104
E. R A WORTH ALLEN
FIG. 3. Low power electron micrograph of a differentiating muscle cell containing a nucleus (N),
elongated mitochondria (m), long polyribosomes (arrows) and an early nonstriated myofibril. Areas of
probable fusion are indicated by the large arrowheads, x 6,000. (After Allen and Pepe, 1965).
noted that myotubes in vitro possess a basal
lamina after the fifth day in culture.
Monucleated cells are devoid of this surface coat, hence its presence is suspected
of preventing further developmental fusion (Fischman, 1972). An ultrastructural
feature of the cultured myotube is the
numerous free 5-6 nm cytofilaments or
cortical filaments found not to bind HMM
antibody as does actin (Ishikawa, et al,
1969). Since these filaments are found particularly near the ends of growing
myotubes and also in nonmyogenic cells
they are thought not to be involved in
myofibrillogenesis.
SYNTHESIS AND APPEARANCE OF MYOFILAMENTS
Early investigators of muscle differentiation were extremely limited by the
techniques available to them. The resolv-
ing power of the electron microscope,
necessary to see myofilaments within
myofibrils, did not enter the field until the
middle 1940's (Hall, et al, 1946).
Prior to investigations of rat skeletal
muscle morphogenesis by Bergman
(1962), myofibrils were believed to be initially formed by some mysterious sarcoplasmic condensation and polymerization
(Van Breeman, 1952; Hibbs, 1956; Godman, 1958). Waddington and Perry (1963)
reported the presence of long helical arrangements of ribosomes in the sarcoplasm of developing frog skeletal muscle
cells. Behnke (1963) simultaneously reported these ribosomal configurations in
differentiating small intestine cells of rat
fetuses. Later that same year, working with
rabbit reticulocytes, Rich coined the term
polyribosomes for chains of protein synthesizing ribosomes (Rich 1963). HeussonSteinnon (1964), described a close association between polyribosomes and developing muscle protein. In 1965, Allen and
Pepe showed a morphological correlation
between the appearance of thick, myosin
myofilaments and long polyribosomes containing 50-60 ribosomes in a chain.
Hey wood and co-workers (1967) isolated
and biochemically identified nascent
myosin from the long polyribosomes. Immunochemical methods were also used to
identify the nascent myosin (Allen and
Terrence, 1968), using an antibody previously prepared against and shown to be
selective for localizing myosin within embryonic chick somites (Holtzer, et al,
1957). The studies of Hey wood and Rich
(1968) demonstrated the synthesis of
myosin, actin, and tropomyosin to be on
polyribosomes of sizes expected from the
molecular weights of the respective subunits.
Myosin
Nascent peptides of varying size ranges
interact to form myosin molecules. Obinata
et al., (1966) reported two sizes of myosin
(light and heavy) in embryonic chick muscle and suggested the smaller of the two
gives rise to the larger. The size of a
peptide synthesized by a polyribosome of
SKELETAL MUSCLE DEVELOPMENT
the size indicated by Hey wood et al. (1967)
and Allen and Terrence (1968) has been
correlated with the heavy subunitof myosin
(Fredericksen and Holtzer, 1968; Lowey,
etai, 1969; Paterson and Strohman, 1970).
When muscle cultures were used as a model,
one set of myosin subunits were found in
mononucleated cells and yet another size
range in multinucleated cells. Others were
commom to both systems (Chi et al., 1975).
Although much useful information is obtained in vitro, the studies of Hilfer et al.
(1973) and Holtzer et al. (1975) have emphasized the caution that should be taken
when attempting to extrapolate in vitro
experimental results with normal events
occuring in vivo. Disregarding the correlation of initially appearing myosin subunits
in vivo with the tryptic digestive products
light and heavy meromyosins, we know the
total myosin molecule is a very large protein possessing a molecular weight of approximately 470,000. We can also calculate
the number of molecules in a thick filament to be around 400. Since thick filament fragments are not observed in vivo,
there must be a very rapid assembly of the
myosin molecules within the thick filaments. Figure 4 represents an electron
micrograph from a negatively stained
homogenate of an embryonic chick somite.
A thick and part of a thin filament are seen
side by side.
Actin
In 1949, Kesztysus, et al. prepared antibodies to the two major muscle proteins.
Localization studies done by tagging the
antibody with fluorescein isothiocyanate,
placed actin with I bands /Holtzer, et al.
1957). There has been much controversy
over the time of the initial appearance of
the protein and or the 6 nm filaments
containing actin ever since. The early
studies of Holtzer et al. (1957) demonstrated a simultaneous appearance of
myosin and actin filaments during
myogenesis in cultured muscle although
later studies of developing muscle in vitro
indicated an earlier appearance of actin
(Heywood and Rich, 1968). Ultrastructural
studies did not clarify the contradictions,
105
as studies of salamander muscle (Hay,
1963) and chicken leg muscle (Fischman,
1967), both indicated a simultaneous appearance of the two muscle filament sizes
(thick-myosin, thin-actin). Other studies,
however, have indicated an earlier appearance of the thin, 6 nm, actin filaments
(Allen and Pepe, 1965; Obinata^a/., 1966;
Przybylski and Blumberg, 1966; Hilfer et
al., 1973; Murphy, 1977). Biochemical
studies, using precipitin tests, had previously shown actin to appear prior to
myosin in developing whole chick embryos
(Ogawa, 1962), when testing for free
molecules as well as myofilaments.
Numerous studies have shown actin
(Tilney, 1976-1977), as well as myosin, (see
review by Pollard and Weihiog, 1974) to be
a protein constituent of various nonmuscle cells. In culture, these cytofilaments
are found predominantly beneath plasma
membranes, primarily at the ends of growing myotubes. They are suspected to be
involved in cytoplasmic streaming (Fischman, 1972). Ishikawa (1968) and Kelly
(1969) further complicated the myofilament controversy by describing 10 nm
filaments called "intermediate filaments"
that do not bind the antibody to heavy
meromyosin as does actin (Ishikawa et al.,
1969). The intermediate size filaments
have also been observed in non-muscle
cells (Ishikawa et al., 1969), but have not
been encountered in more recent in vivo
studies (Hilfer et al, 1973; Murphy, 1977).
This author believes, as suggested earlier
(Allen, 1973a; Hilfer et al., 1973), that
slight differences found in in vivo and in
vitro myogenic processes, which ultimately
lead to identical sarcomeres, may account
for varying sequential differences described in the literature. Observing negatively stained homogenates as well as
routinely embedded and sectioned chick
somites, Allen and Pepe (1965) demonstrated an early myogenic age where
thin but no thick filaments could be seen.
The earlier appearance of actin filaments
in developing chick myotome cells is observed routinely in my laboratory and
many of these randomly oriented thin
filaments virtually saturate the sarcoplasm
of in vivo somitic muscle cells prior to the
FIG. 4. Electron micrograph of a negatively stained
homogenate from somites of a 3 day chick embryo.
Approximately 400 myosin molecules are present in
the isolated thick filament. The broken thin filament
contains 2 helically wound strands of globular actin
monomers, a strand of tropomyosin, and periodic
troponin molecules, x 140,000 (After Allen, 1973a).
107
SKELETAL MUSCLE DEVELOPMENT
appearance of thick filaments. The 6 nm
thin filaments are morphologically identical to those isolated from adult skeletal
muscle and purified actin preparation
(Hanson and Lowey, 1963; Allen and
Pepe, 1965).
Minor muscle proteins
Tropomyosin and troponin are regulatory proteins closely associated with the
thin, actin filament. Very little has been
reported concerning their development.
Heywood and Rich (1968) found polyribosomes, presumably synthesizing tropomyosin in vitro, appearing in development during later stages of embryogenesis than either actin or myosin. In
cervical somites of chick embryos,
Hirabayshi (1971), detected the presence
of tropomyosin at the same time as actin
and myosin. Results by Hitchcock (1970),
indicate a deficiency in both tropomyosin
and troponin prior to 14 days of incubation, 11-12 days after actin and myosin
have been detected. Fischman (1972),
suggested the possibility of the two regulatory proteins being present but in an
inactive form. This suggestion appears
very probable since a definite correlation
exists between troponin, which is associated with tropomyosin, and the sarcotubular system (Hitchcock, 1970). The
tubules are not organized into a final form
reported for adult skeletal muscle, until
late in development. Recent studies of
chick dystrophic muscle support this possibility (Murphy, 1977). Murphy (1977)
found a lack of an organized sarcotubular
system and scarcity of troponin antibody
binding in developing dystrophic chick
embryos as compared with similar age
normal chick embryos.
Other minor muscle proteins have been
isolated from myofibrils, viz, a actinin,
/3-actinin, M-protein, but studies concerning their development have been neglected. It has been demonstrated, however,
that M-lines, containing M protein, are
detected within sarcomeres of the chick
just prior to or almost simultaneous with
the appearance of typical cross striations
(Allen and Grisnik, 1971).
THE MYOFIBRIL
Thin, actin containing filaments approximately 6 nm in diameter, appear in developing chick skeletal muscle prior to
myofilaments of any other size range. The
actin filaments increase in number and
virtually saturate the sarcoplasm of
myogenic myoblasts before a single thick
(myosin) filament can be seen. When only a
few initial thick filaments are detected,
they are not observed singly, but surrounded by many thin ones (Allen and
Pepe, 1965; Fischman, 1967). Fischman
(1967) suggests that myofilament properties leading to aggregation may also be
responsible for spatial arrangements. In an
investigation of actin filament polarity during initial stages of myofibril assembly,
Shimada and Obinata (1977) found thin
filaments exhibiting the right polarity and
spatial position similar to that seen in mature muscle. They suggested an immediate
interaction between diick and thin filaments similar to that indicated earlier by
Allen (19736). This initial attraction (actomyosin reaction) would inevitably lead to
an early hexagonal array of thin filaments
surrounding thick ones.
Soon after a cluster of hexagonally arranged thick and thin filaments appear,
they become linearly arranged in the longitudinal axis of the cell, predominantly
near the cell's periphery (Allen and Pepe,
1965). The mechanism of linear grouping
(see Fig. 3) is not known. Allen and Pepe
(1965) showed the crude myofibrils to be
traversed by membranous tubules at regular periodic intervals of 1.5/im, forming
segments comparable in length to a thick
filament and/or an A band. This description of non-striated myofibrils forming
prior to striated ones is not a new concept
(Godlewski, 1902; Weed, 1936; Holtzer et
al, 1957; Allen and Pepe, 1965; Allen,
19736). Holtzer (1961), stated in a review
of myogenesis, that every striated myofibril
is preceded by a brief non-striated period.
Ezerman and Ishikawa (1967), first demonstrated a tubular system, thought to be
the T-tubule component of skeletal muscle, formed by inward invaginations and
branchings of the sarcolemma in develop-
108
E. RAWORTH ALLEN
ing muscle cultures. These studies were
the first of many such investigations (see
review by Franzini-Armstrong, 1972). Early
nonstriated myofibrils are often found
near the periphery of myogenic cells, thus
the invaginating tubules (Ezerman and
Ishikawa, 1967; Allen 19736), may be instrumental in the initial myofibrillar
alignment. Allen and Pepe (1965), using
chick muscle and Walker and Edge (1971),
using rat muscle, demonstrated that the
periodic tubules of the early myofibril are
followed by a close association of a Z-line
material. Studies of guinea pig, rabbit, cat,
dog, goat, and sheep cardiac muscle
(Sommer and Johnson, 1968) as well as
amphibians (Warren, 1973), have all indicated a close association between an enveloping tubular system and early Z-lines.
This association is indicated in Figure 5.
Many workers, both in light and electron
microscopy, have demonstrated that a
Z-line is the first form of a cross striation to
appear on myofibrils (Weed, 1936; Van
Breeman, 1952; Hibbs, 1956; Shafig,
1963). The inpocketing, branching and
enveloping tubular system may also explain the lateral register seen in Z lines on
neighboring myofibrils (Walkers al., 1968).
In the studies of Walker and Edge (1971),
it was further shown that electron-opaque
strands were seen connecting the tubules
to forming Z-lines. The strands may represent the thin "Z filaments" (Knappeis and
Carlsen, 1962), or the connecting mechanism proposed by Kelly (1969), for
connecting thin filament tips to Z bands. If
there is an attraction as well as connection
function, then these filaments may help to
explain the observed linear aggregating of
hexagonally arranged myofilament clusters. The longitudinal growth by merestimatically adding new non-striated sarcomeres to the ends of striated fibrils (Holtzer, 1961), adds strength to this possibility.
This author feels, as first suggested in 1965
(Allen and Pepe, 1965) and again in 1973
(Allen, 19736), that these early Z bands
form an attachment or anchoring point for
the thin, actin myofilaments. The passive
pulling apart of 1.5/*m periodic Z lines
(thick filament length) during growth
would give a typical A, I, H banding pat-
tern. As demonstrated in Figure 6, the I
bands would form on either side of the
central A band and an H zone would be
visualized in the center. Both bands are
and would be the result of thin filaments
sliding past thick ones to follow attached Z
lines. Holtzer (1970) stated that relationships between thick and thin filaments
necessary to form a central H band in the
sarcomere, may be dependent upon the
presence of the Z line. Using antibody
staining, he also could detect developing A
bands prior to visualizing Z lines with
FIG. 5. Electron micrograph of an early myofibril
striated only with a periodic tubular system and
associated Z-line material. Note the close association
between the two. x 36,000.
SKELETAL MUSCLE DEVELOPMENT
m
FIG. 6. Diagrammatical representation of sarcomere formation in vivo, (a) Initial appearance of 1.5
fim segments (A band length) traversed by a periodic
tubular system, (b) Z-lines have formed in association
with the tubular system and provided anchor points
for thin filaments. Z lines pull away and result in a
"typical" straited banding pattern.
phase microscopy. A pulling apart of the
Z-lines and thus the filaments would increase the size of the sarcomere, and this is
the recorded observation (Allen, 19736). A
developmental sequence such as the one
described previously would mean that our
terminology for aspects of muscular contraction may develop backwards. Skeletal
muscle sarcomeres first appear in the "contracted" state, and secondarily, due to Z
lines pulling apart, become "relaxed."
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