A M . ZOOLOGIST, 7:435-449 (1967).
Diversity of Striated Muscle
GRAHAM HOYLE
Department of Biology, University of Oregon, Eugene 97403
SYNOPSIS. A broad comparative survey has been made correlating ultrastructure of
cross-striated fibers with contractile properties in both invertebrates and vertebrates.
Most of the muscles were found to be heterogeneous in fiber-composition as indicated
by: length of sarcomere, extent of SR, number of invaginating tubules, numbers of
mitochondria, etc. Z discs and M bands have markedly different structures in
different fibers. The general concept of the "fibrillar" nature of striated muscle is
challenged. It is suggested that following excitation the responses of individual sarcomeres, or parts of sarcomeres, are relatively independent. The possibility that all
striated muscles contain a very thin elastic filament in parallel with actin and niyosin,
which may also be contractile, is raised.
There have been a great many symposia
on muscle in recent years, largely aimed at
building up a picture of the structure and
function o£ a hypothetical, generalized,
functional unit. As a result, such a general
picture has emerged. The purpose of the
present symposium is to examine some of
the rich diversity to be found in the muscles of a variety of organisms, both vertebrate and invertebrate, with a view both to
illuminating the body of "basic" knowledge
and also critically evaluating it. If it is
truly universal it should be possible to understand the diversity as variations on the
theme. But if there are serious discrepancies
the comparative physiologist should question the validity of the general model.
We may recognize five principal aspects
of muscle: ultrastructure and molecular
architecture, chemistry, dynamics, neural
control, and contraction-coupling.
The field of muscle chemistry is a specialized, complex one which, unfortunately, is
still somewhat remote from contact with
other aspects. For the most part it has been
omitted from the topics to be presented
at this meeting. With the exception of molluscan muscles, which have been of great
interest historically to comparative physiologists, our attention will be confined
largely to striated muscles, We shall first
consider the ultrastructural components
Supported by research grants: GB 3160 from
National Science Foundation and NBO 381904 from
the U. S. Public Health Service.
and molecular architecture of a variety of
striated muscles and the light this throws
on the molecular mechanism of contraction
(Aubert, Jean Hanson, Reedy, Pat McNeill, Walcott, Ridgway).
Next, continuing to pursue lines which
have been of great interest to comparative
physiologists, arthropod neuromuscular
mechanisms will be reviewed by Atwood
and Usherwood. Peachey and Smith will
consider morphological features related to
excitation-contraction coupling. Molluscan
muscle will be covered by Millman and
Betty Twarog. Reuben, Ashley, Selverston
and Edwards will consider physiological
aspects of excitation-contraction coupling.
Problems of dynamics in heart muscle will
be reviewed by Brady, and giant barnacle
fibers by Abbott and myself. There are surprising similarities between the development of active state in some invertebrate
skeletal muscles and vertebrate heart muscles, which do not follow the classical
model of A.V. Hill. Baskin will give an account of work on changes in volume during
contraction and Pringle and Abbott have
kindly agreed to present overviews and
criticism in a formal way. A link to littleconsidered aspects of muscle chemistry will
be made through Van der Kloot.
In our laboratory in Eugene, Oregon,
and at the marine laboratories in Friday
Harbor, Washington, and Coconut Island,
Hawaii, we have been making correlated
ultrastructural and physiological studies on
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436
GRAHAM HOYI.E
a variety of striated muscles. So far we have
examined the following:
VERTEBRATE—rabbit, psoas, sartorius;
garter snake, "slow" body-wall, "fast" bodywall; frog sartorius, gastrocnemius; gecko,
sartorius, toe; fish, main fin.
INVERTEBRATE—crab, Cancer magister, accessory flexor, extensor of dactyl "fast",
"slow", intermediate fibers; crab, Podophthalmus, eyestalk levator—white and pink
fibers; crab, Paralilhoides, leg; crab, Partunus, leg "fast", "slow", various intermediate fibers; squid, Loligo, mantle; insect, Benacus, flight, siphon retractor; insect, Scltistocerca, extensor tibiae, spiracular
closing, anterior coxal adductor; insect,
Periplaneta, extensor tibiae; copepod, Doropygus seclusus, antennal; barnacle, Balanus
nubiluSj depressors—white and pink fibers,
adductors.
The task of describing all this material
in a formal way is gargantuan and presents
formidable difficulties in publication. 1 will
refer to it in this introductory talk only in
a general way, drawing upon selected examples from our experience in an attempt
to give an overall picture and to raise
questions. A total of five matters relating- to
our generalized concept of structure and
function of striated muscle will be considered.
The first point to raise is our growing
awareness of the inhomogeneity of muscles.
In cold-blooded vertebrates (Kuffler and
Vaughan Williams, 1953) and birds (Ginsborg, i960) it is now well-established that
muscles may contain specialized "slow"'
and "fast" fibers. This has not yet been
clearly established for mammals, except
possibly for intrinsic eye muscles (Hess and
Pilar, 1963), although here the "slow"
fibers are perhaps not strictly comparable
to frog "slow" fibers. However, there are
marked differences in the lipid-staining
reactions of individual mammalian fibers
(Gauthier and Padykula, 1965; George and
Susheela, 1961) as well as in invertebrates
(George and Bhakthan, 1961). Some are
apparently enzymatically lipolytic, while
their immediate neighbors utilize only carbohydrate. Others are intermediate. There
are probably associated gross physiological
differences, resulting in effectively "fast"phasic, "slow"-tonic, and intermediate
forms. Such differences have been positively
established by detailed analysis of single
fibers in several crustacean muscles (Atwood, this symposium; Hoyle, 1967, in
preparation; Atwood, et ah, 1965).
In the latter, we now have examples of
muscles in which the different kinds of fiber
occur mixed together (extensor muscles of
walking legs) and others in which they are
segregated into distinct bundles (accessory
flexor—Cancer; anterior rotator of paddle—
Portunus; levator of eyestalk—Podophthalmus). The different fibers may be dramatically different in regard to length of
sarcomere. For example, in a minute
copepod muscle comprising three or four
fibers, one fiber has a sarcomere length of 4
yu., while its neighbors are 12 ^ (Fig. la).
Such fibers have twitch times which are
roughly proportional to the logarithm of
the length of the A band: 40 ms, 200 ms,
and 600 ms, respectively (Hoyle, in preparation) . The twitch of the whole muscle
is a statistical sum, in this case a simple
one, but enormously complex in a larger
muscle. Another example of the kinds of
differences we are beginning to find between adjacent fibers is shown in Fig. lb.
The muscle is the extensor tibiae of Periplaneta americana. There are several conspicuous differences, but the most notable
is in regard to thin filaments, which are
very numerous in one fiber, but sparse in
the other. The various portions of a large,
complex muscle may be separately innervated and function independently. Or
they may receive branches from the same
axon and function together (Dorai-Raj,
1964). However, the different fibers can
still function to some extent independently,
as a result of different pattern sensitivities
of their neuromuscular junctions. The
smallest striated fibers occur in coelenterates
and are about 1 p in diameter. The largest
ones occur in giant barnacles and king
crabs, reaching a maximum of 5 mm in
diameter. There are intrinsic problems in
the excitation of such large fibers, which
DIVERSITY OF STRIATED MUSCLE
437
FIG. la,b. Differences in adjacent fibers in small
muscles, a. Longitudinal section through a small
copepod muscle containing two, possibly three, different kinds of muscle fiber in the same very small
muscle. Magnification about X 3000. The narrow
sarcomeres are 4 /i long, the wide ones about 12 p.
Note different widths of Z discs; clear H zones are
present in short sarcomere fibers, but not in long
sarcomere ones. Micrograph courtesy ot Dr. W. H.
Fahrenbach. b, Transverse section through two
muscle fibers in extensor tibiae of Periplaneta
americana. One has a large number of actin filaments, the other very few. There are also differences in the SR. Some clusters of actin filaments
stand alone (arrows). Neither diads nor transverse
tubules may be found in the fiber having few thin
filaments. X 42,000.
will be discussed by Selverston and Peachey.
Turning our attention now to the details
of individual fibers, we find it necessary to
question the universal use of the term
"fibril" to designate a discrete sub-unit of
a fiber. Some "Fibrillenstruktur" fibers appear in transverse section to be divided
neatly into clusters of myofilaments each
surrounded completely by sarcoplasmic
reticulum (SR) . A close inspection, however, always reveals one or a few gaps in
the continuity of this sarcoplasmic reticular
"skin" (Fig. 2). Even if one particular section does not reveal such a gap for any
given cluster, another section farther along
the same sarcomere is very likely to do so.
Furthermore, if we attempt to trace the
same "fibril" for more than a few sarcomeres
we find that we cannot do so. Over a few
segments the SR envelope comes to envelop
quite different sets of filaments. Insect
"fibrillar" flight muscle may be the only
exception.
At the other extreme, in some "Feklerstruktur" fibers, there is very little SR at
all (Hess, 1965; Hoyle, et al, 1966). All
kinds of intermediates exist in some mixed
muscles. Some fibers have long, radiating
strips of SR, making the fiber look like the
wheel of a sports-car.
It is clear that striated muscle in general
is better considered as being composed of
a mass of myofilaments which is invaded to
a greater or lesser extent by sarcoplasmic.
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GRAHAM HOVLE
DIVERSITY OF STRIATED MUSCLE
439
FIG. 2. Trans\erse sections through tspical vertebrate striated muscle fibers. Xote that adjacent
"fibrils" are connected to each other by bridges,
a, Fish tail muscle (Tramatomus bernachii Boulanger). Note that adjacent sarcomeres are not in
line, the section passing through two H zones, three
overlap zones, and two I bands, b, Rabbit psoas.
Here the arrangement of filaments in the overlap
/one is aupical. M\osiiv> are ver\ thick and surrounded by large, irregular groups of thin filaments. A section through a Z disc is included,
showing the square, window-field arrangement of
filaments. X 30,000.
FIG. 3. Nature of Z discs, a. Fish tail muscle (T.
bernacchii) showing "classical" zig-zag arrangement
of linkage between actin filaments from adjacent
sarcomeres, densely-staining, b, Garter snake, ribs
to body wall. Overlapping arrangement with
lateral cross-connections, c, Copepod larva, anten-
nular muscle. Very little structure and no density.
Some thin filaments are cross-linked, others appear
to go straight across, d, Locust (Schistocerca), extensor tibiae. Alternating attachments of thin filaments, but broad band with numerous cross-connections. X 120,000.
FIG. 4. Nature of M bands, a, Rabbit psoas.
Three or five parallel sets of bridges are visible.
Note also the complex, overlapping nature of the
Z disc, b, Insect (Benacus), fibrillar flight muscle.
Five to seven parallel sets of bridges, c, Locust
(Schistocerca), extensor tibiae. Wide sarcomere at
rest here but slightly stretched. The whole region
shown is the H zone. Cross connections occur
randomly over the whole region, d, Crab (Podo-
phthalmut), white eye-raising fiber. Center of the
H zone is bare; two zones of cross-bridges occur,
each in rows of 3-5. e, Cross-section of M band of
fish tail muscle, showing connecting bridges, f,
Cross-section of H zone of stretched depressor fiber
of barnacle (B. nubilus). Random cross-connections;
these probably occur throughout the A band.
All X 80,000.
FIG. 5. Arrangements of thin and thick filaments, jumping leg. 4:1 ratio (orbits of 10). f, Crab (Poda, Garter snake. 2:1 ratio approximates classical ophthalmus), pink eye-raiser fiber. 7:1 ratio. No
regular orbits of thin filaments. The fiber was
model, but is somewhat loose, b, Insect flight
(Benacus). 3:1 ratio, extremely regular arrange- stretched and showed H zones; the high ratio and
ii regular arrangement are natural and do not repment. Thick filaments have a double ring structure, c, Rabbit psoas, classical arrangement, d, resent the result of a double overlap of thin filaCopepod larva, antennulary muscle. 3:1 ratio re- ments. All X 100,000. 5b, courtesy of B. Walcott.
sembles insect flight muscle, e, Locust (Schistocerca),
FIG. 6. Longitudinal section through ribs-skin
muscle fiber of garter snake fixed in a state of isometric contraction. Note the uneven nature of
contractions of individual sarcomeres—or rather
parts of half-sarcomeres (the basic functional unit).
Some are shortened, others extended. X 12,000.
reticulum, which is anastomosing in three
dimensions. When the SR is very extensive,
a superficial appearance is given in transverse sections of a complete division.
My second consideration is the nature of
Z discs (Kxause's "membranes"). These are
still referred to in important articles as
"membrar.es" (Huxley, 1965) and even assigned a significant functional role as conductors of excitation inwards (Garamvolgi,
1963). It is now abundantly clear, however,
that no known Z disc resembles, in its fine
structure, a cellular element which a membrane physiologist would recognize as a
source of ionic separation. Also, classical experiments have demonstrated that oil
droplets pass very freely through Z discs.
Secondly, Z discs come in great variety.
Some are thin, others five times as thick.
Patricia Dudley has found very fast-contracting, beautifully-striated muscles in a
copepod larva which completely lack any
dense Z line in most of their sarcomeres
(Fig. 3c).
We have found that lipid solvents readily
remove the density from the Z discs in vertebrate fibers. What is left closely resembles
the appearance of the I band of the copepod fibers in the relevant Z region,
namely, a set of fine filaments, some of
which appear to be thinner than actin.
In some Z discs, there is a zig-zag appearance in which alternate actins from
contiguous sarcomeres are cross-connected
by thinner filaments which may be single
actin strands, or another material (Fig. 3a).
Such discs have a "basket-weave" appearance in transverse section {e.g., Reedy,
440
GRAHAM HOYLE
DIVERSITY OF STRIATED MUSCLE
1964, who suggested the term). Other discs
show an overlap of actin filaments or of extensions from them, which are thinner than
actins (Fig. 3b). Discs of this kind are crossconnected by fine filaments in a simple
square array, forming a "window" pattern
in transverse section. Yet other discs seem
to be composed only of a dense mass of fine
filaments running longitudinally, together
with many fine lateral connections (Fig.
3d).
A third question concerns the means of
linking thick filaments together. Some muscles, such as frog and fish, have a set of
three to five rows of cross-bridges located
exactly in the center of the H zone forming
the M band region (Fig. 4a). Insect flight
muscle is similar, but has more rows of
bridges. In transverse section they present
a neat hexagonal pattern (Fig. 4e). However, in other muscles such as the copepod
antennal and Podophthalmns
eye-raiser,
the center of the sarcomere is clear but
there is a double M band, comprised of
two sets of bridges, one on each side (Fig.
4d). Cross-connections between the myosin
filaments occur at many sites, possibly along
their entire length (Fig. 4f).
The fourth issue is the relationship of
actin to myosin filaments. The first fibers in
which the filaments were clearly seen were
from rabbit psoas and blowHy flight muscle.
The former have a 2:1 actin/myosin ratio,
the latter a 3:1 ratio (Fig. 5a, b). In each
case the actins are in neat orbits. Such an
array has been considered to be associated
intimately with the mechanism of contraction. Now we can add fibers to the list
in which the ratio is 4:1 providing orbits
of 10 (locust extensor tibiae—Fig. 5e), and
5:1 (several insect and crab muscles) providing orbits of 12 (see also Auber, this
symposium). However, the orbits are by no
means neat and regular when they are also
large. Some contain as few as 4 thin filaments, others as many at 20. To the list we
can add a special kind of fiber found in the
eyestalk levator muscle of Podophthalmus
in which there is a 7:1 ratio of thin to thick
(Fig. 5f). Here there is virtually no orbiting. The actins form small clusters of
441
6-40 filaments arranged irregularly, or in
places in a "square" array, while the myosins fall very irregularly between them and
may even have no actins around them.
Thus, a neat array is not an essential
feature of the molecular architecture of a
striated muscle fiber.
The fifth point concerns the dogma that
striated muscle contains only two longitudinally-arranged filamentous proteins, actin
and myosin. Upon this belief rests the need
to invoke cross-bridges between them as the
basis for both development of tension and
changes in length. How firmly established
in this generalization? Muscles do not fall
apart, nor do they show any sudden fall
in stiffness when stretched to just beyond
the point of overlap. This could be because
the elastic strength of the sarcolemma, and
perhaps also the SR, hold the contractile
apparatus together. However, fibers from
which the sarcolemma has been stripped
behave in a similar manner, and Hanson
and Huxley (1956) have reported that
single rabbit fibrils from which the myosin
had been removed may remain intact and
are elastic. Allen Selverston, in our lab, was
able to stretch a split glycerinated fibril
from Balarms niibilns in the presence of
ATP, to well beyond the overlap point
(Fig. 7). There was no chance in this
experiment that SR could be holding
the material together. Of considerable interest is the fact that the sarcomeres did not
stretch equally. Some retained almost rest
length, while others reached about 3X rest
length. The latter became quite thin, yet
still did not break.
Such fibrils return to their original shape.
Electron micrographs made of similar
stretched material show that although the
A-band of heavily-stretched sarcomeres is
somewhat elongated due to a partial separation of filaments (they are displaced but
not stretched), there is a marked gap between it and the T-band filaments at both
ends (Fig. 8). There was also a gap in
some instances between the Z disc and the
1 filaments. The gaps must be bridged
by fine elastic filaments.
In their original proposal regarding the
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GRAHAM HOYLE
DIVERSITY OF STRIATED MUSCLE
443
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GRAHAM HOYLE
DIVERSITY OF STRIATED MI'SCI.F.
445
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GRAHAM HOYLE
filament composition of striated muscle,
Hanson and Huxley (1956) proposed a
hypothetical elastic, very thin filament,
which they labelled the S filament, joining
the ends of the actin filaments across the
H zone. They also proposed a similar unnamed filament linking the other ends of
the actin to the Z discs. Both filaments were
dropped from their definitive accounts,
however.
I would like to propose, not that we return to this model, but rather that we replace it by a different one with which their
earlier suggestions are simply compatible.
On this model there is a third filament,
which I propose to call the T filament, extending from one end of the fiber to the
other, passing through Z discs and H zones
alike (Fig. 9). T may stand for very thin.
The T filament must be highly elastic,
and therefore must play an important
passive role in muscle. The length of the
series elastic component in barnacle muscles, as determined at the peak of contractibility, is about 14% of the total rest
length. This is so long that it can only be
explained on the basis that it is provided
by a component of the sarcomeres. This
finding, together with the end-to-end location and undoubted sti-ength of the T filament, suggests the possibility that it is also
concerned with contraction.
We have embarked upon a series of investigations aimed at attempting to identify
T filaments in various muscles. Some of
these will be described by my colleagues,
Patricia McNeill, Benjamin Walcott, and
Ellis Ridgway. Suffice to say that I am now
satisfied that such a filament exists, although the demonstration is very difficult
in view of its extreme thinness.
In regard to its possible contractibility,
all attempts to show that contraction fails
at the point of non-overlap, which is reFIG. 7. Single split myofibril from glycerinated
lateral depressor of B. nubilus stretched in the
presence of ATP. Note the uneven nature of the
changes in length of sarcomere. Three sarcomeres
are stretched beyond the overlap point of actin
and myosin filaments, yet do not break (see electron micrographs in paper by McNeill and Hoyle).
This micrograph, courtesy of A. Selverston.
DIVERSITY OF STRIATED MUSCLE
447
filaments. The gap is bridged by very thin (T)
filaments. Micrograph, courtesy of A. Selverston.
k
FIG. 8.
tudinal
unit of
beyond
Low-power electron micrograph of longisection through a single sarcomere of a
a B. nubilus lateral depressor stretched
the point of overlap of thick and thin
quired by the theory that cross-bridges
alone are responsible, have failed,—even
the most sophisticated and carefully-controlled ones (Gordon, Huxley, and Julian,
1966 a and b). Giant barnacle fibers
stretched under load to twice their resting
length — about 30% beyond the overlap
point — will still contract extensively when
depolarized by KC1. The forces developed
at lengths beyond overlap are small, but
they cannot be ignored.
There is one last matter to which I
would like to draw your attention. All of
our ideas regarding the functioning of
striated muscle derive from experiments on
specialized fast muscle fibers of the frog.
The ideas have never been adapted to explain slower and graded contractions which
are of equal significance. It is not known
what constitutes a graded contraction in
micro-anatomical or molecular terms. Does
it involve partial, but equal, activations of
each sarcomere, or are individual sarcomeres activated to varying extents?
We have attempted to answer these
questions by rapid fixation for electron
microscopy of fibers while stimulating them
to develop graded contractions. The contractions were monitored by a tension
recorder, and the membrane potential by
an intracellular electrode. Most of the
fibers treated in this way, from material
as diverse as snake and barnacle, have
shown similar appearances in the electron
microscope. That is, individual sarcomeres,
or even parts of half-sarcomeres, are heavily
contracted, while others ranged through
rest-length to heavily stretched (Fig. 6).
To explain these findings I have proposed
that the fundamental unit in excitationcontraction coupling is a single cisternal
element of the SR (Hoyle, 1966). Either
the cisternal elements or units (C. Us)
have a range of thresholds or the amount
of calcium released by each is directly proportional to the local potential difference
(or current flow), or both possibilitites may
occur. In a graded contraction only a proportion of the C. Us are excited, perhaps
448
GRAHAM HOYLE
to different extents, resulting in a very
heterogeneous set of microanatomical
changes—but graded tension. A conventional "all-or-none" twitch would result
from a rapid, nearly synchronous firing of
all the C. Us.
During the course of these investigations,
I have found fibers which are in a state of
partial (as much as 30%) contraction at
normal resting potentials. These fibers give
quick relaxations (negative twitches) in
response to hyperpolarizing pulses. Other
fibers have been found which contract in
response to hyperpolarizing pulses of
adequate strength, and yet others which
contract strongly when a hyperpolarizing
current is turned off, but not during its
passage. None of the currently accepted
models of excitation-contraction coupling
can explain all of these diverse findings
without qualifications.
For comparative physiologists all of what
I have said may have significance, though
much of it will be controversial. It has
long been clear, however, that the current
orthodoxies regarding muscle ultrastructure
as well as the hypothesis of the molecular
basis of contraction and the mechanism of
excitation-contraction coupling, should
not be regarded as established without a
great deal of further comparative study.
Likewise, the notions of active state developed by the A.V. Hill school may need to
be seriously questioned. If we can examine
closely and come to fully understand some
of the remarkable variety of ultrastructures
and associated physiological function found
in different muscles we are bound to illuminate our total understanding of this
most important and fascinating tissue.
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FIG. 9. Diagram to show proposed model of striated muscle structure including an elastic very thin
(T) filament running the whole length of the
sarcomere (and possibly the fiber). Actin and
myosin filaments run parallel to the T filaments.
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DIVERSITY OF STRIATED MUSCLE
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