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Journal of Electromyography and Kinesiology 12 (2002) 425–433

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Considerations on muscle contraction
W. Herzog ∗, R. Ait-Haddou
Faculty of Kinesiology, University of Calgary, 2500 University Dr. N.W., Calgary, AB, Canada, T2N 1N4

Abstract

The independent force generator and the power-stroke cross-bridge model have dominated the thinking on mechanisms of muscu-
lar contraction for nearly the past five decades. Here, we review the evolution of the cross-bridge theory from its origins as a two-
state model to the current thinking of a multi-state mechanical model that is tightly coupled with the hydrolysis of ATP. Finally,
we emphasize the role of skeletal muscle myosin II as a molecular motor whose actions are greatly influenced by Brownian motion.
We briefly consider the conceptual idea of myosin II working as a ratchet rather than a power stroke model, an idea that is explored
in detail in the companion paper.
 2002 Elsevier Science Ltd. All rights reserved.

Keywords: Skeletal muscle; Sliding filament theory; Cross-bridge theory; Brownian motion; Molecular motors; Mechanisms of contraction; ATP
hydrolysis; Muscle energetics; Molecular ratchet

1. Background tein folding remained the primary mechanism for muscle
contraction until the early 1950s.
The following text is largely based on a lecture we H. Huxley [17] was the first to suggest that contraction
gave at the European Congress on Sports Science, in may occur through the relative sliding of two sets of
Cologne, July 2001. The lecture had two principal pur- filaments. This so-called “sliding filament theory” was
poses. The first purpose was to provide an overview of independently confirmed by H. Huxley and Hansen [19]
the current thinking governing the molecular mechanism and A. Huxley and Niedergerke [15] using isolated
of muscular contraction, the cross-bridge theory, while myofibrils and phase contrast microscopy and single
the second purpose was to draw attention to the limi- fibers and interference microscopy, respectively. The
tations of the current mechanism, and to propose an question then became, what makes filaments slide?
alternative way of how muscular contraction might
occur. This paper will follow the same format.
Before diving into the foundations of the cross-bridge 2. The 1957 formulation of the cross-bridge theory
theory, we should like to point out that the proposed
mechanism of muscular contraction has changed com- In 1957, A. Huxley [13] formulated a theory that pro-
pletely over the past century. At the beginning of the posed how filaments slide past each other. The theory
20th century, the so-called lactic acid theory was based was based on several properties that had been observed
on the idea that contraction was caused by the lactic in muscle experiments. First, Ramsey and Street [27]
acid-induced folding of long protein chains along the performed experiments on single fibers of frog and
muscle fibers. This theory was disproved when it was showed that isometric force reached a maximum at an
discovered that muscle poisoned with iodacetic acid average sarcomere length of about 2 µm. When increas-
could produce contraction and force without lactic acid ing the length beyond 2 µm, they found a nearly linear
[21]. Even with the death of the lactic acid theory, pro- decrease in force, with zero force occurring at about 4.2
µm (Fig. 1). This result suggested that force production
might be directly related to the amount of myofilament

Corresponding author. Tel.: +1-403-220-8525; fax: +1-403-284- overlap. Second, Hill [11] reported that the relationship
3553. between the speed of shortening and the total rate of
E-mail address: walter@kin.ucalgary.ca (W. Herzog). energy liberation was a rectangular hyperbola (Fig. 2).

1050-6411/02/$ - see front matter.  2002 Elsevier Science Ltd. All rights reserved.
PII: S 1 0 5 0 - 6 4 1 1 ( 0 2 ) 0 0 0 3 6 - 6
426 W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433

Fig. 3. The structure of ATP.

Fig. 1. Tension developed by an isolated frog muscle fiber on stimu-
lation at different lengths. Points: Ramsey and Street [27]. Line: Ford
et al. [7] (with permission).

Fig. 4. Schematic illustration of the 1957 model of the cross-bridge
theory (adapted from Huxley [13], with permission).

assumed to attach to specialized sites (A) on the thin
filament. Attachment and detachment of the side pieces
was thought to occur in a cyclic fashion, therefore great
shortening of the muscle could occur through a series of
small steps. Each time a side piece M is attached to a
corresponding A site, force is transmitted between the
Fig. 2. Rates of energy liberation in excess of the steady rate during
two filaments because of the force in the elastic springs
an isometric contraction, as determined by A.V. Hill [11] (with
permission). of the M piece, except if M is at its equilibrium position
where strain (and force) in the springs was assumed to
be zero.
Needham [26] pointed out that Hill’s [11] observation How do we now get directed force from a system as
could readily be explained by active sites in a muscle shown in Fig. 4. If we assume that M attaches spon-
that operate in a cyclic manner, similar to an enzyme taneously to A, as Huxley did, then one would assume
causing a chemical reaction. Third, adenosine triphosph- that the probability for a detached cross-bridge to attach
ate (ATP, Fig. 3) was discovered in muscle extracts [20], to an actin site is equal to the probability of its location
and was shown to be hydrolyzed by actomyosin [4]. (x, Fig. 4). It can be shown that the probability distri-
These findings hinted at the central role of ATP as the bution of M’s location undergoing Brownian motion is
fuel for muscle contraction. a Gaussian shape about the equilibrium position. There-
In the formulation of the cross-bridge theory, A. Hux- fore, a cross-bridge would likely attach to the actin at a
ley [13] assumed that thick filaments (myosin) had side location where strain in the springs is relatively low, thus
pieces (M) that were connected via elastic springs to the force would be low as well. Similarly, from the structural
thick filament (Fig. 4). These side pieces were thought symmetry of the system, it follows that M would attach
to oscillate about their equilibrium point (O) because of to A with equal probability for A being located on the
thermal agitation (Brownian motion). Side pieces were left and right of the cross-bridge equilibrium position.
W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433 427

Therefore, on average, the actin filament would undergo (almost) uniformly over the range [⫺0.5la, 0.5la], where
a zero displacement relative to the myosin filament. la is the distance between actin attachment sites. The pro-
Obviously, such a system cannot produce directed mus- portion of attached cross-bridges, n(x, t), is now a func-
cle force and shortening. In order to produce a directed tion of x and t, and the rate of change in n(x, t) is
movement of actin relative to myosin (such that muscle obtained as the material derivative:
shortening and directed force production could occur),
Dn ∂n ∂n
Huxley [13] introduced the idea that the rate of attach- ⫽ ⫹ v (3)
ment (f) and detachment (g) were dependent on the x- Dt ∂t ∂x
location (Fig. 4) of the actin attachment site relative to where v is assumed to be negative for muscle shortening.
the cross-bridge equilibrium position. These rate con- The governing differential equation, assuming that the
stants had to be chosen asymmetrically in the sense that two myofilaments are perfectly rigid, becomes:

冉 冊
the attachment probability of a cross-bridge had to be
greater for positive x-values (thus, cross-bridge attach- ∂n ∂n 1
⫹ v ⫽ ⫺n f(x)⫺ng(x) (4)
ment would cause muscle shortening) than for negative ∂t ∂x Ia
x-values. Huxley’s asymmetrical choice is shown in Fig.
Eq. (4) may be solved using the method of characteristic
5. No explanation was given as to how this asymmetry
curves [5,35].
may be produced.
If we now consider, as Huxley [13] did, a great num-
ber of M–A pairs that have one and the same x-location
3. The 1969 formulation of the cross-bridge model
at each instant in time, the proportion of attached cross-
bridges, n(x), is a function of time exclusively. By defi-
So far, the cross-bridge head (M, Fig. 4) was thought
nition of f(x) and g(x), the rate of change of n(x) over
to be in a single configuration. However, Reedy et al.
time becomes:
[30] demonstrated that cross-bridges at rest were about
dn perpendicular to the filament axis, while cross-bridges
⫽ (1⫺n)f(x)⫺ng(x) (1) in rigor were tilted 45° to the perpendicular rest con-
dt
figuration. Based on this information, H. Huxley [18]
For a dynamic equilibrium state (i.e., dn/dt=0), we find proposed that the cross-bridge head (subfragment 1)
that the number of attached cross-bridges, neq, is given attaches to the thin filament, and force and filament
by the probability of attachment: transport would be generated by a tendency of the head
f(x) to rotate about its attachment point (Fig. 6). Therefore,
neq ⫽ (2) subfragment 1 was assumed to act as a crank, pulling
f(x) ⫹ g(x)
the thin relative to the thick filament. Subfragment 2,
So far, we have assumed that all cross-bridges have the that connects subfragment 1 to the backbone of the thick
same value x at each instant in time, t. However, for a
great number of cross-bridges, x(t) would be distributed

Fig. 5. Rate functions for the formation, f, and the breaking, g, of
cross-bridge links between the thick (myosin) and the thin (actin)
myofilaments as a function of x, the distance from the active site on
the thin filament to the equilibrium position of the cross-bridge Fig. 6. Diagram of the mechanism of force generation by a cross-
(adapted from Huxley [13], with permission). bridge as proposed by Huxley [18] (with permission).
428 W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433

filament, acts as a connecting rod, converting the rotary
movement of the cross-bridge head into a linear dis-
placement of the filaments. The idea of the cross-bridge
power stroke was born.

4. The 1971 formulation of the cross-bridge theory

A. Huxley and Simmons [16] observed that when a
muscle fiber is shortened rapidly, force drops virtually
simultaneously with the length change, and then recovers
in two distinct phases, a quick and a slow phase (Fig. 7).
Huxley and Simmons [16] defined the force transients
associated with a quick shortening step with two charac-
teristic variables, T1 and T2. T1 was defined as the mini-
mum force achieved during the rapid shortening step. T2
was defined as the force at the end of the quick recovery
phase. T1 was found to vary almost linearly with the
magnitude of the step, reaching zero force at a step Fig. 8. Values of T1 (the extreme tension reached after a quick short-
ening step; see Fig. 7) and T2 (the tension reached during the early
amplitude of approximately 6 nm per half-sarcomere
tension recovery after the step) as functions of the size of the step
(Fig. 8). T2 remained nearly the same as the isometric (from Ford et al. [7], with permission).
force just prior to the length step, T0, for step amplitudes
of up to about 5 nm, but then started to become progress-
ively smaller with increasing step amplitude, reaching
zero force (i.e. the early, quick recovery was completely
absent) at step amplitudes of 13 nm per half-sarcomere
and beyond.
The interpretation of these results is summarized in
the model shown in Fig. 9. The key features of this
theory are that the shortening force response is associa-
ted with an elastic element and occurs in steps. The elas-
tic element was associated with the link AB1 (AB2) in
Fig. 9, and this elastic link accounts for the virtually
instantaneous change in force with shortening (Fig. 10).
The quick recovery of force following the shortening
step was associated with a rotation of the (still attached)
cross-bridge head from a position of small affinity
between M–A attachments (M1A1) to increasingly
greater affinities between M–A for stable states M2A2, Fig. 9. Diagram to illustrate the assumptions in the theory of Huxley
and Simmons [16]. The bond between M3 and A3 is stronger than that
between M1 and A1, favoring position B2 over B1. Likewise, the bond
between M4 and A4 is stronger than that between M2 and A2. The link
AB is elastic (from Huxley and Simmons [16], with permission).

M3A3, and M4A4 (Fig. 9). Rotation of the cross-bridge
head through these different attachment states would
stretch the elastic link (Fig. 10), and so provide a quick
force recovery. For step amplitudes greater than about 13
nm per half-sarcomere, all attached cross-bridges were
assumed to have detached, therefore, the quick recovery
offered by cross-bridge head rotation was lost, and only
Fig. 7. Record of changes in length and tension when a sudden
decrease of length (6 nm per half-sarcomere) is imposed on an isolated a slow force recovery was possible that was governed
frog muscle fiber during contraction at 0 °C (from Ford et al. [7], by the (slow) rate of attachment of the cross-bridges to
with permission). the actin attachment sites.
W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433 429

the attachment point of the cross-bridge to actin. How-
ever, in a series of structural studies [28,29], it was sug-
gested that the connection between the cross-bridge head
(subfragment S1) and actin does not allow for rotation,
but that rotation takes place through a conformational
change of the light-chain binding domain about a hinge
within the myosin head.
Specifically, the following sequence of events was
proposed for muscular contraction (Fig. 11). Starting

Fig. 10. Schematic illustration of the presumed events associated
with a rapid release and the following quick recovery of force. (a) The Fig. 11. Proposed molecular mechanism of contraction. (A) Rigor
cross-bridge head is in its initial position and the elastic link is conformation. The narrow cleft that splits the 50 kD segments of the
stretched. (b) A rapid release has occurred. The cross-bridge head is myosin heavy-chain sequence into two domains is closed (horizontal
in the same orientation as in (a) but the elastic link has shortened gap, perpendicular to the actin filament axis). (B) Addition of ATP,
because of the relative movement of the myofilaments. The cross- and initial binding of ATP to the active site, causes an opening of the
bridge force (carried by the elastic link) is smaller in (b) than in (a). narrow cleft and disrupts the strong binding between actin and myosin,
(c) The cross-bridge head rotates to a position of lower potential but still allows for weak binding. The actin and myosin dissociate. (C)
energy, thereby stretching the elastic link and increasing the cross- The final binding of ATP to myosin causes a closure of the nucleotide
bridge force without any myofilament movement. binding pocket and a corresponding configurational change of the myo-
sin molecule. ATP is now hydrolyzed. (D) Myosin can now reattach
to actin, presumably in multiple steps. The narrow cleft closes to pro-
5. Current thinking duce strong binding. Phosphate, P, is released, and the power stroke
starts. (E) During the power stroke, the myosin molecule reverses its
conformation change induced by ATP binding, the active site pocket
In the 1969 and 1971 models of the molecular mech- is reopened, ADP is released and the rigor conformation is established.
anisms of contraction, cross-bridge rotation plays an The cross-bridge cycle can now start over again. (From Rayment et
important part. This rotation was thought to occur about al. [29], with permission.)
430 W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433

from the rigor conformation, Rayment et al. [29] sug- The binding of ATP catalyzes the dissociation of myosin
gested that the narrow cleft that splits the 50 kD seg- from actin [3,32]. When dissociated, ATP is hydrolyzed,
ments of the myosin heavy chain sequence into two and the cross-bridge head goes through a conformational
domains is closed (Fig. 11A, horizontal gap, perpendicu- change (the recovery stroke, Fig. 12). Myosin attaches
lar to the actin filament axis). Addition of ATP, and to actin, phosphate is released, and the power or working
initial binding of ATP to myosin at the active site causes stroke is initiated. ADP is released, establishing the rigor
an opening of the narrow cleft between the upper and conformation. ATP then attaches to the myosin head,
lower domains of the 50 kD segments. This event, in myosin can now dissociate from actin, and the cycle
turn, disrupts the “strong” binding between actin and may restart.
myosin, but still allows for a “weak” attachment (Fig. Obviously, there are variations from the above pro-
11B). The final ATP binding to myosin causes a closure posed theory of contraction, however Figs. 11 and 12,
of the nucleotide binding pocket and a corresponding and Table 1 represent the most accepted thinking at
change of the myosin molecule. Myosin now detaches present. An interesting variation of the above ideas was
from actin and ATP is hydrolyzed (Fig. 11C). Rebinding proposed by A. Huxley [14] who suggested the possi-
of myosin to actin can now occur, presumably in mul- bility of cross-bridge rotation about its attachment point
tiple steps. The gap between the upper and lower domain on the actin filament. Another important aspect of the
closes in this process to produce strong binding, and scheme discussed above is that the rate limiting step of
phosphate, P, is released. This event starts the power the cross-bridge cycle occurs in the attachment of myo-
stroke (Fig. 11D). During the power stroke, the myosin sin to actin (Table 1). The remaining steps in the
S1 reverses its conformational change induced by ATP hydrolysis cycle are considered much faster than the
binding, the active site pocket is reopened, ADP is attachment rate.
released, and the rigor conformation is established (Fig.
11E). The cross-bridge cycle can now be restarted by
ATP binding to myosin. 6. Limitations
The detailed reactions of myosin S1 with actin and
ATP are not known because not all of the rate constants The detailed mechanical steps of muscle contraction,
have been determined. However, combining the struc- as well as the details of the actin–myosin hydrolysis
tural evidence [28,29], the biochemical data measured cycle are not known. And to cite A. Huxley [14]:
in solution [2,8–10,22–24,31], and the mechanical data
[6,16], it is possible to infer the likely actin–myosin the whole history of muscular contraction during the
hydrolysis cycle (Table 1). Superimposing the biochemi- last half century shows that even when a set of ideas
cal cycle with a schematic structural model for the seems to be well established, there is a large chance
hydrolysis cycle (Fig. 12) gives the current thinking of that it will be overthrown by some unexpected dis-
how muscular contraction might occur. covery.
Starting from the top left drawing in Fig. 12, and fol-
lowing the arrows (the likely path of the actin–myosin With this quote in mind, we should continuously ask
hydrolysis cycle), we go through the following steps. ourselves, what are the limitations of the current thinking

Table 1
Actin–myosin hydrolysis cycle (rabbit skeletal muscle). (Adapted from Howard [12], with permission)

(+8 kT) (0) (⫺12 kT) (⫺15 kT) (⫺17 kT)
ⱖ104 s⫺1 103 s⫺1 20,000 s⫺1
A·M·T A·M·D·P → A·M·D , A·M , A·M·T
100s-1 2000 s⫺1
30 s⫺1 300 s⫺1 0.2 s⫺1↓ ↓1 s⫺1 0.4 s⫺1 2000 s⫺1
100 s⫺1
M·T , M·D·P → M·D M ← M·T,
10 s⫺1 0.1 s⫺1 苲10⫺4 s⫺1
(0) (⫺2 kT) (⫺8 kT) (⫺6 kT) (⫺25 kT)

M, myosin; T, ATP; D, ADP; P, phosphate; A, actin. The most commonly followed path is shown in bold type. In parentheses are the approximate
free energies of the states assuming [ATP]=4 mM, [Pi]=2 mM, [ADP]=20 µM. The actin concentration is taken to equal 1 mM, its concentration
in skeletal muscle (this is fairly arbitrary because the effective concentration in a muscle depends on the accessibility of the actin site to the myosin
head). Overall ATPase: kcat=25 s⫺1, KM(ATP)=10 µM, KM(actin)⬵100 µM (low ionic strength) at 20 °C [2]. The rate constants are based on
experimental data taken from isolated S1 and/or myofibrils under roughly physiological ionic strength. The values vary by up to a factor of 10
between laboratories. The constants (K) are dissociation constants and k+(k⫺) is the rate constant in the clockwise (counterclockwise) direction
(from Howard [12], with permission).
W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433 431

Fig. 12. Schematic illustration of the current thinking of the cross- bridge cycle, including a best estimate of the rate constants of the reactions
(adapted from Howard [12], with permission).

on muscle contraction, and is the set of well established cannot be readily explained by a power stroke model of
ideas still the best in view of newly emerging experi- muscle contraction.
mental results? As a microscopic molecular motor, the myosin head
One of the things that has troubled us is the asym- operates at energy levels that are just a little greater than
metry of the rate constants in a seemingly perfectly sym- the random thermal energy of the surroundings. These
metrical model in the 1957 theory (Figs. 4 and 5). Of thermal baths are essential for the process of the chemi-
course, the asymmetry was required, otherwise there cal reactions. The myosin head is exposed to these ther-
would have been no net force and no net sliding of the mal forces that arise from collision with molecules in
actin relative to the myosin filament. However, no reason the surrounding fluid. Because of the random occurrence
was provided why, from a biological point of view, the of these collisions, in terms of direction and magnitude,
rate constants for attachment and detachment of the the cross-bridge head will undergo a random diffusion,
cross-bridges were asymmetrical. Although, in more or Brownian motion. In the detached state, the myosin
recent models, structural arguments for this asymmetry head moves more or less freely, and therefore, undergoes
have been proposed, none seems terribly convincing. a free Brownian motion. In the attached state, the ran-
Other questions arise from experiments on single mol- dom diffusion is limited by the force field of the actin
ecules. For example, if contraction occurs as sche- filament. The transition between the two diffusive modes
matically proposed in Figs. 11 and 12, one would expect is driven by the chemical reaction of ATP hydrolysis.
that the relative sliding of actin and myosin during a Therefore, the movement of the cross-bridge head has
single powerstroke could be calculated from the angular to be stochastic in nature and must be described by a
reorientation and the magnitude of the lever arm. How- reaction–diffusion equation. Note that thermal diffusion
ever, it is known that the myosin subfragment 1(S1) has was part of the cross-bridge theory from its conception
a shorter neck than the double-headed HMM construct. [13].
Assuming, as has been done, that the neck region of the At first glance, it may appear that Brownian motion
cross-bridge acts as the lever arm that determines the could be quite disruptive and may greatly affect the
step size of a single power-stroke, one would expect a efficiency of events such as muscular contraction. How-
smaller step size from S1 compared to HMM. However, ever, contrary to this intuitive thinking, it appears that
such a difference was not found [25]. Similarly, Yanag- the myosin head can extract work from the thermal bath
ida [33] found that step sizes remained about the same if the system is far from equilibrium and if there is a
for myosin II molecules with normal neck lengths, and structural asymmetry in the geometry of the system. A
molecules in which the neck region was reduced to 20% system that extracts work under these two conditions is
of its normal length. Furthermore, Yanagida [33,34] known as a thermal ratchet. We will investigate these
found that myosin II had a step reversal in about 10% of systems in much more detail in the following paper on
all steps observed. These results, although preliminary, ratchet-type mechanisms of molecular movement,
432 W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433

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[6] Finer JT, Simmons RM, Spudich JA. Single myosin molecule Nature 1965;207:1276–80.
W. Herzog, R. Ait-Haddou / Journal of Electromyography and Kinesiology 12 (2002) 425–433 433

[31] Siemankowski RF, Wiseman MO, White HD. ADP dissociation Rachid Ait-Haddou received his MSc in
from actomyosin subfragment 1 is sufficiently slow to limit the Applied Mathematics from the University
unloaded shortening velocity in vertebrate muscle. Proc Natl Mohamed V, Rabat, Morocco, in 1991, and his
Acad Sci U S A 1985;82:658–62. PhD in Applied Mathematics from the Univer-
sity Joseph Fourier, Grenoble, France, in 1996.
[32] Szent-Györgyi AG. Contraction of myosin threads. Stud Inst Med
He is currently a postdoctoral scientist wih Dr.
Chem Univ Szeged 1941;1:17–26. Herzog at the University of Calgary. His
[33] Yanagida T. Simultaneous observation of individual ATPase and research interests are in the area of biomolecular
mechanical events by a single myosin molecule during interaction motors and biological transport phenomena,
with actin. Canmore Symposium on Skeletal Muscle; Canmore, mechanisms of muscle contraction, and approxi-
Alberta; 1999. p. 22. mation theory.
[34] Yanagida T. Personal communication; August 2000.
[35] Zahalak GI, Ma SP. Muscle activation and contraction: constitut-
ive relations based directly on cross-bridge kinetics. J Biomech
Eng 1990;112:52–62.

Dr W. Herzog is a full Professor in Kinesiology
and Engineering with an adjunct appointment in
Medicine at the University of Calgary. He
received his BSc (equivalent) from the Federal
Technical Institute of Zurich, his PhD in Bio-
mechanics from the University of Iowa in 1985,
and completed a 2-year postdoctoral fellowship
in Biomechanics at the University of Calgary in
1987. His primary research interests in the area
of muscle mechanics include the theoretical
modelling of molecular events of force pro-
duction, skeletal muscle properties, and the con-
trol of synergistic muscles during cyclic movements.