J. Appl. Physiol.

88: 1127–1132, 2000.

invited review
Form follows function: how muscle
shape is regulated by work
BRENDA RUSSELL, DELARA MOTLAGH, AND WILLIAM W. ASHLEY
Department of Physiology and Biophysics, College of Medicine,
University of Illinois at Chicago, Chicago, Illinois 60612

Russell, Brenda, Delara Motlagh, and William W. Ashley. Form

follows function: how muscle shape is regulated by work. J. Appl. Physiol.
88: 1127–1132, 2000.—What determines the shape, size, and force output
of cardiac and skeletal muscle? Chicago architect Louis Sullivan (1856–
1924), father of the skyscraper, observed that ‘‘form follows function.’’
This is as true for the structural elements of a striated muscle cell as it is
for the architectural features of a building. Function is a critical evolutionary
determinant, not form. To survive, the animal has evolved muscles with the
capacity for dynamic responses to altered functional demand. For example,
work against an increased load leads to increased mass and cross-sectional
area (hypertrophy), which is directly proportional to an increased poten-
tial for force production. Thus a cell has the capacity to alter its shape as
well as its volume in response to a need for altered force production.
Muscle function relies primarily on an organized assembly of contractile
and other sarcomeric proteins. From analysis of homogenized cells and
molecular and biochemical assays, we have learned about transcription,
translation, and posttranslational processes that underlie protein synthe-
sis but still have done little in addressing the important questions of
shape or regional cell growth. Skeletal muscles only grow in length as the
bones grow; therefore, most studies of adult hypertrophy really only involve
increased cross-sectional area. The heart chamber, however, can extend
in both longitudinal and transverse directions, and cardiac cells can grow
in length and width. We know little about the regulation of these
directional processes that appear as a cell gets larger with hypertrophy or
smaller with atrophy. This review gives a brief overview of the regulation
of cell shape and the composition and aggregation of contractile proteins
into filaments, the sarcomere, and myofibrils. We examine how mechani-
cal activity regulates the turnover and exchange of contraction proteins.
Finally, we suggest what kinds of experiments are needed to answer
these fundamental questions about the regulation of muscle cell shape.
sarcomere; myofibril; assembly; hypertrophy; cardiac and skeletal muscle

REGULATION OF CELL SHAPE plished by incorporation of new material throughout

the entire cross-sectional area of the cell (33). Length-
We know that trees add new rings of growth under
the bark each year as the trunk grows bigger and the wise growth of a muscle cell occurs by addition at the
tips of the branches extend as it grows taller. What does tips (18), presumably because the crystalline architec-
a muscle cell do as it grows? Surprisingly, we still do not ture would make it hard to splice a new unit of length
have the answer to this fundamental question of how (the sarcomere) into the middle of the existing contrac-
muscle grows. Autoradiography and ultrastructural tile mass. However, we do not know what mechanisms
studies suggest that increased cell width is accom- regulate growth in either the circumferential or longitu-
dinal direction.
Muscle growth and adaptation is a complex and
Second in a series of invited mini-reviews on ‘‘Molecular integrative process. The cell has an arsenal of regula-
and Cellular Basis of Exercise Adaptations.’’ tory steps that can be used in response to growth
http://www.jap.org 8750-7587/00 $5.00 Copyright r 2000 the American Physiological Society 1127

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1128 INVITED REVIEW

signals. Gene transcription is followed by the processes tubular removal have not been done in vivo. It is
of translation and assembly of proteins into the contrac- possible that, in the whole muscle, the myofibrillar
tile architecture such that the function is optimized for architecture is sufficiently dense so that microtubular
the task at hand. The upregulation of transcription and transport is essential to overcome restricted diffusion.
translation of contractile genes is regulated by work; Therefore, it remains to be seen if local translation is a
therefore, the cell size can easily be doubled (2, 12). major regulatory mechanism for adjustment of cell
Moreover, this doubling is accomplished while the shape.
stoichiometry of all proteins is preserved and the
THE SARCOMERE
correct appearance of every element of the sarcomere is
maintained. Remember, a muscle cell is three dimen- Cardiac and skeletal muscles are both composed of
sional; therefore, a cell is able to double its volume longitudinal arrays of thick and thin filaments in a
either in width or in length (Fig. 1). Note that the repeating unit called the sarcomere. For a complete
addition of sarcomeres end-to-end in series makes the discussion of muscle structure, we refer the reader to
cell longer, whereas the addition of sarcomeres side-by- Gray’s Anatomy (14). According to the sliding filament
side in parallel makes the cell wider. The direction of theory, the thick filament protein myosin attaches to
growth is not controlled by transcription so it must be a actin, a component of the thin filament, and force is
posttranscriptional process, such as translation or as- developed as a result of ATP-dependent movement of
sembly. the two filaments past one another. There are numer-
One hypothesis for controlling the site at which new ous other proteins in the sarcomere whose roles are for
sarcomeres are assembled is based on the potential for modulation of contraction, for maintenance of the struc-
delivering the messenger RNA (mRNA) to specific ture, or for both. Many of these proteins do not appear
cellular locations. For example, if the message could be in text books so we have diagrammed their location (not
delivered to the ends of the myocyte and translated to scale) in Fig. 2. To complicate matters further, many
there, then a cell would preferentially elongate. The of these proteins come in slightly different amino acid
myosin heavy chain (MHC) is 200 kDa and, like other sequences known as isoforms. Functional variations
large intracellular proteins, cannot diffuse quickly from can be achieved by combinations and amounts of vari-
its site of synthesis for incorporation into sarcomeres. ous isoforms and can be readily switched by alteration
Indeed, differential localization of sarcomeric and cyto- of activity patterns or hormone stimulation (9, 23). We
skeletal mRNAs is seen in muscle during development do not go into these isoform characteristics in detail
and periods of rapid growth (reviewed in Refs. 25 here because they do not determine cell shape.
and 26). We have studied this in skeletal and cardiac Cardiac muscle and skeletal muscle are similar in
cells. Stretching a rabbit’s leg makes mRNA accumu- that they are both striated muscle; however, there are
late at the tips of the elongating fibers as they grow many important differences between the two (Table 1).
longer. Furthermore, transport of mRNA via microtu- Many of these differences in form arise from the
bules to its respective subcellular destination in the significant differences in the functional requirements of
periphery of a cardiac cell only occurs when there is the two types of muscle. The fundamental difference is
active contraction and ongoing translation (22). We that skeletal muscle is designed to do intermittent,
found that cardiac muscle cells can rapidly assemble unidirectional work against load or gravity with the
sarcomeres throughout the cell even when the mRNA is force being transmitted through tendonous attach-
centrally located and microtubules are gone, suggest- ments. Cardiac muscle, however, works continuously
ing that diffusional rates for the message or the protein and is designed to squeeze blood out of a chamber
is adequate. However, similar experiments with micro- without the use of tendons. Furthermore, the term
myofibril refers to myofilaments bundled during devel-
opment or by the sarcoplasmic reticulum in the adult
skeletal muscles. It is not often realized that this kind
of cylindrical bundling does not occur in adult cardiac
muscle, where the myofilaments are grouped into huge
irregular fields named felderstrucktur by German
anatomists of the nineteenth century. Interdigitating
thick and thin filaments are the working units in the
sarcomere; therefore, to keep the function clear, we
usually refer to the term sarcomere instead of the term
fibril or myofibril. Even more confusing are the terms
concentric and eccentric. Concentric work is defined as
Fig. 1. A muscle cell can double its volume by increasing in either the production of active tension while the muscle is
width or length. This diagram shows a cell beginning with 2 shortening. Eccentric work in skeletal muscle is de-
sarcomeric units of several thick and thin filaments. This cell can fined as production of active tension while the muscle is
double in length by the addition of sarcomeres end-to-end in series, lengthening. In skeletal muscle, concentric work occurs
making the cell longer, or it can double in width by the addition of
sarcomeres side-by-side in parallel. Direction of growth is not con-
when a weight is lifted against gravity and eccentric
trolled by transcription; therefore, it must be a posttranscriptional work occurs when a weight is lowered in a controlled
process such as translation or assembly. fashion. The term eccentric in the cardiac literature

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 INVITED REVIEW 1129

Fig. 2. Arrangement of proteins in the

sarcomere. Backbone of the thin fila-
ment is actin with decoration by tropo-
mysoin and the troponin complex. Its
length is set by the long nebulin mol-
ecule (or nebulette for the heart). Turn-
over and growth of a thin filament may
be regulated by its attachment to ␣-ac-
tinin at the Z band, by a capping pro-
tein at its free end, or by mechanical
activity coincident with the modulation
of the troponin complex (see text). Thick
filament is made mainly of myosin
heavy chain with its associated light
chains. Its turnover and growth length
may be regulated by the binding of C
protein and also by mechanical activ-
ity. Central location of the thick fila-
ment in the sarcomere is determined
by the long titin molecules that span
from the thick filament to the Z band
(see text).

arose from the anatomic position in the chest that increase the functionality of muscle. In the latter case,
occurs when the volume of blood returning to the heart however, the form changes are maladaptive and corre-
(preload) is greater than the ejected fraction. Under late with disease.
these conditions, cardiac muscle must contract while
being stretched by an increased volume of blood. Con- ASSEMBLY OF THE SARCOMERE AND THE MYOFIBRIL
centric refers to the conditions that occur when the
heart must contract against a greater afterload (i.e., In striated muscle, assembly of the sarcomeric pro-
blood pressure). Eccentric work and concentric work teins into highly organized sarcomeres is an ordered
are the same in both cardiac and skeletal muscle, but and complex process sometimes called sarcomerogen-
the results are quite different. In skeletal muscle, esis. Formation of the first fibril (myofibrillogenesis) is
eccentric exercise is the most potent stimulus for the process for bundling the thick and thin filaments
functional hypertrophy, leading to bulkier and stronger together (1, 10). Assembly of myofilaments, in vivo,
muscles. In cardiac muscle, eccentric hypertrophy leads requires a complex array of structural and associated
to long, thin, weak muscle cells. The anatomy of the proteins. In culture, a striated muscle cell initially
skeletal muscle allows it to accommodate the stretch- looks more like a fibroblast or smooth muscle cell with
ing that occurs during eccentric work while maintain- actin stress cables anchored at the membrane and
ing functional cross bridges. interspersed with dense Z bodies containing ␣-actinin
Cardiac muscle cannot accommodate significant (6). This observation has been confirmed in living
stretch as effectively as skeletal muscle and maintain cultures by the use of green fluorescent protein conju-
functional cross bridges. This discussion points to an gated to ␣-actinin (4, 24). The first short thin filaments
important distinction. In skeletal muscle, eccentric composed of actin, tropomyosin, and the troponin com-
hypertrophy is generally a physiological adaptation plex extend in both directions away from the Z bodies,
that leads to beneficial changes in function. In the making I-Z-I brushes linked to each other by the long
heart, eccentric hypertrophy is a pathological change titin molecule (28). In cultured cells, myosin binding C
that occurs as the heart enters irreversible failure. The protein clamps the rod region nonmuscle myosin IIB to
direction in which the heart cell grows has major form the initial thick filaments in the cytoplasm nearby
clinical consequences for the mechanical output from (4, 24, 29). The NH2 terminus of titin binds to the Z line,
the whole heart. In pressure overload, the heart wall and the COOH terminus binds to the center of the thick
thickens, and cells develop a large cross-sectional area filament, thereby linking the loose, nonstriated arrange-
(corresponding to concentric hypertrophy), whereas, in ments of I-Z-I complexes and capturing the isolated
response to a volume overload, the heart wall becomes thick filaments to form the sarcomere. Alignment of the
thin with elongated cells (corresponding to eccentric sarcomeres in the transverse plane is achieved by the
hypertrophy) (17). Thus form still follows function, but arrival of myomesin and M protein between the thick
in one case the changes in form are adaptive and filaments and cytosketetal proteins to form the Z bands

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1130 INVITED REVIEW

Table 1. Comparison of function and composition top like the yolk in vitro. Given that cultured cells are
of cardiac and skeletal muscles flattened on the surface of the dish, this is hardly
surprising that this adaptation to the new environment
Cardiac Skeletal yields many nonphysiological properties in the cell.
Rest Cycles 24 h, over 60 Intermittent (maxi- However, when myofibrillogenesis was observed in vivo
beats/min mum for respira- in normally situated cells in early development of the
tory muscles over heart of the chick embryo by confocal microscopy, a
10 beats/min)
Load increase Pressure overload Weight lifting
difference in the sequence of the appearance of sarco-
from high periph- meric proteins was found. No stress fibers or premyofi-
eral resistance brils were observed in vivo, suggesting that these
Length increase Volume overload by Bone growth or findings could be an artifact supported by the artificial
over-filling cham- stretch two-dimensional properties of the current cell culture
bers
Eccentric Contraction in over- Contraction during system (7). In studies of new sarcomere formation in
filled chamber: extension: very elongating skeletal muscle, myofibrils formed well away
long, thin cells wide cells from lateral association with the membrane. There
Concentric Contraction in Contraction during were actin stress fibers, Z bodies, and insertion to a
normal or small shortening: wide
chamber: short cells
focal adhesion at the end of the fiber only (5). Therefore,
wide cells we cannot assume that the observation on fibril forma-
Cell size Diameter of 10–15 Diameter of 10–100 tion in the flattened cells in culture holds for the
µm; length of µm; length varies three-dimensional architecture in vivo.
⬎100 µm up to many cm
Nuclei One (or two) central Multiple peripher- MECHANICAL REGULATION OF PROTEIN TURNOVER
nuclei ally located nuclei
Stem cells No Yes, satellite cells AND EXCHANGE
Apoptosis Yes, heart failure Yes, disuse or
atrophy All biological materials are constantly in a state of
Fibrils No, irregular field Yes, cylindrical flux, with a cycle of molecules entering and leaving
like bundles; bundles; fibrillen- every structure. Therefore, a sarcomere today will not
felderstruktur struktur be made of the same molecules as tomorrow (21). To
Myosin heavy chain ␣-MHC Slow/type I: ␤-MHC;
isoforms ␤-MHC fast/type II: 2X,
understand such replacement at the level of the contrac-
2A, 2B tile machinery, contractile proteins have been labeled
Myosin LC1 MLC1a; MLC1v MLC1v; MLC1/3fast and followed (8, 24, 26). These exchange processes have
Myosin LC2 MLC2a; MLC2v MLC2v; MLC2fast not been measured directly in vivo except by isoform
Myosin binding pro- MBP-Ccardiac MBP-Cslow exchange as witnessed by immunoelectron microscopy.
tein-C MBP-Cfast
Actin ␣-actincardiac ␣-actinskeletal The natural incorporation of the newly synthesized
Tropomyosin ␣-Tmcardiac ␣-Tmslow ␣-MHC was detected in a day or two, and, notably, the
␣-Tmfast exchange rate was greater near the free ends of the
␤-Tm thick filaments than in the center (32). Tropomyosin is
TnC TnCcardiac TnCcardiac
TnCfast
also preferentially replaced at the ends of the thin
TnI TnIcardiac TnIslow filaments (20), suggesting that the ends of filaments
TnIfast are less tightly bound than the central regions.
TnT TnTcardiac TnTskeletal Every protein has its own steady-state exchange rate
MHC, myosin heavy chain; MLC, myosin light chain; MBP, myosin that varies from seconds to weeks. The contractile
binding protein; Tm, tropomyosin; TnC, troponin C; TnI, troponin I; proteins in vivo are among the longest to live of known
TnT, troponin T. proteins. For example, sarcomeric actin’s half-life is
⬃20 days and MHC turns over with a half-life of 7–10
from the I-Z-I brushes. The final thin filament length of days, whereas the components of the troponin complex
1 µm is determined by the long nebulin molecule in have turnover rates similar to troponin I, troponin T,
skeletal muscle (nebulette in cardiac muscle) and by an and troponin C at 3.2, 3.5, and 5.3 days, respectively
actin capping protein (15). The other long molecule, (19).
titin, appears to be necessary for the determination of However, if a molecule leaves the protection of the
both the length of the thick filament (1.6 µm) and for intact filament, it is highly susceptible to rapid degrada-
bringing it to the center of the sarcomere. This is tion, with a half-life in minutes when disassembled in
evident because titin binds to the Z line at its NH2 both cardiac and skeletal muscles (11, 27). This leads to
terminus and to the M line at its COOH terminus. the question of what processes foster unraveling of the
The first sarcomeres in culture form in close proxim- filaments so that rapid degradation follows. The simple
ity to the membrane and are coupled by focal adhesions answer is removal of the activity or load, for example,
to the extracellular environment. It is worth noting tenotomy of skeletal muscle, space flight for cardiac
that a cardiac myocyte changes from a cylindrical, and skeletal muscle, or separation of tissues into cells
rod-shaped cell in vivo with a central nucleus embed- to culture them. It might not matter whether the
ded in contractile material to one that is shaped like a removal of load is externally or internally generated,
fried egg with the contractile proline lying near the since even inhibition of contractile activity (e.g., by
lower surface like the white and the nucleus sitting on blockade of calcium transients or inhibition of actin-

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 INVITED REVIEW 1131

myosin cross-bridge cycling) reduces the MHC and detection of a larger variety of structures. For example,
actin content of cultured cells and leads to a time- the FLAG peptide (DYKDDDDK) is an improved affin-
dependent disappearance of intact sarcomeres. There ity tag in use for detection and purification of recombi-
is both a decrease in MHC and actin synthesis and an nant antibody fragments (20). Such tagged proteins can
increase in the rate of MHC and actin degradation as be introduced in vitro by transfection (adnenovirus or
sarcomeres disappear (3, 27). These effects are entirely lipofectamine) and are easily detected with the use of
reversible, and an increase in load or activity enhances commercially available antibodies.
assembly of the sarcomere. Passive stretch causes Transgenic animals allow a mutated or tagged pro-
MHC and actin accumulation in contracting cells, due tein to be introduced into the whole animal. With newer
to both an increase in the rate of protein synthesis and expression systems, we can turn these new genes on at
a reduction in the rate of degradation (30). Surpris- a specific time in the adult rather than have them
ingly, cardiac myocytes cyclically stretched are not active throughout embryological development. How-
aligned to the force vector as they would be in any ever, when one is trying to explore cell shape control,
muscle in vivo. Rather, they swing to the perpendicular these do not permit much better experimental control
direction and lie transverse to the axis of strain (29, 30). than do the natural isoform exchange and anatomic
We think this might be due to the abnormal attachment descriptions that were done in past decades. They are
between the culture cells and the slippery surface of the also much more expensive.
supporting membrane. The chemistry and surface fea- The use in whole intact animals has the advantage of
tures adjacent to the cell are important to both cell seeing the real response to altered functional demands
shape and attachment (16, 29). in vivo and, therefore, will always be essential. Unfortu-
To study the mechanics of the cross bridge, methods nately, cardiac mechanobiological research is ham-
were developed to allow exchange of the natural contrac- pered because interventions in vivo cause the death or
tile proteins with those engineered by molecular tech- demise of the experimental animal, whereas studies in
niques (20). New proteins can be driven into the vitro do not yet have a life-like cell culture system. As
filaments by the law of mass action if they are supplied we strive to understand the fundamental mechanisms
at many times the normal concentration in vitro or of mechanical transduction at the cellular level, there is
overexpressed in transgenic animals. Almost nothing a strong need to create more physiologically relevant
goes in at physiological concentrations; therefore, high models of cells in vitro. Specifically, to understand cell
concentrations are needed for mass action to work shape, we must address questions of how contractile
effectively. For example, the isolated, skinned muscle function in cells modulates addition of new contractile
strips can have 80% of the troponin sites occupied with filaments in parallel or series. Our notion is that the
the new protein and be functioning 1 h later. We can ultimate shape of individual myocytes is the fundamen-
glean other useful information from the methods sec- tal process by which the muscle cells grow and remodel
tions of this series of mechanical papers and see that to meet altered work demands.
turnover rates may well vary in different mechanical
conditions. For example, the affinity of troponin T to We gratefully acknowledge discussions with our present and
tropomyosin, which governs the resting exchange rate, former colleagues, only some of whose work we are able to cite in this
brief review.
is more rapid in rigor when the myosin head is tightly This research was supported over the years by the American Heart
bound to actin (for a review, see Ref. 31). Perhaps Association, the Muscular Dystrophy Association, and National
stabilization of the thick filaments can be regulated in a Institutes of Health (currently Grant HL-40880 to B. Russell).
similar manner by the phosphorylation or calcium Address for reprint requests and other correspondence: B. Russell,
binding through associated thick filaments proteins, Dept. of Physiology and Biophysics (M/C 901), Univ. of Illinois at
Chicago, 835 S. Wolcott Ave., Chicago, IL 60612–7342 (E-mail:
such as the C proteins (34). Relative binding affinities [email protected]).
could well link calcium regulation of contractility to
favor either assembly or disassembly.
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