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Considerations on the history dependence of muscle

contraction
Dilson E. Rassier and Walter Herzog
Journal of Applied Physiology 96:419-427, 2004. doi:10.1152/japplphysiol.00653.2003

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on the following topics:
Biochemistry .. Sarcomeres
Biophysics .. Muscle Contraction
Biophysics .. Myofibrils
Physiology .. Cross-Bridges
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J Appl Physiol 96: 419–427, 2004;
10.1152/japplphysiol.00653.2003. Invited Review

Considerations on the history dependence of muscle


contraction

Dilson E. Rassier and Walter Herzog


Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada T2N 1N4

Rassier, Dilson E., and Walter Herzog. Considerations on the history dependence
of muscle contraction. J Appl Physiol 96: 419–427, 2004; 10.1152/japplphysiol.00653.
2003.—When a skeletal muscle that is actively producing force is shortened or
stretched, the resulting steady-state isometric force after the dynamic phase is smaller
or greater, respectively, than the purely isometric force obtained at the corresponding
final length. The cross-bridge model of muscle contraction does not readily explain this
history dependence of force production. The most accepted proposal to explain both,
force depression after shortening and force enhancement after stretch, is a nonuniform
behavior of sarcomeres that develops during and after length changes. This hypothesis
is based on the idea of instability of sarcomere lengths on the descending limb of the
force-length relationship. However, recent evidence suggests that skeletal muscles may
be stable over the entire range of active force production, including the descending limb
of the force-length relationship. The purpose of this review was to critically evaluate

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hypotheses aimed at explaining the history dependence of force production and to
provide some novel insight into the possible mechanisms underlying these phenomena.
It is concluded that the sarcomere nonuniformity hypothesis cannot always explain the
total force enhancement observed after stretch and likely does not cause all of the force
depression after shortening. There is evidence that force depression after shortening is
associated with a reduction in the proportion of attached cross bridges, which, in turn,
might be related to a stress-induced inhibition of cross-bridge attachment in the
myofilament overlap zone. Furthermore, we suggest that force enhancement is not
associated with instability of sarcomeres on the descending limb of the force-length
relationship and that force enhancement has an active and a passive component. Force
depression after shortening and force enhancement after stretch are likely to have
different origins.
force depression; force enhancement; instability; sarcomere nonuniformity

THE CROSS-BRIDGE MODEL OF muscle contraction was proposed cannot be explained directly by the degree of myofilament
by Huxley (38) and was further characterized in experiments overlap in sarcomeres (27).
conducted in his laboratory (41). Together with the sliding In the past two decades, it has been suggested repeatedly
filament theory (39, 40, 42, 43), and strengthened by the that force depression after shortening and force enhance-
description of the sarcomere force-length relationship (27), ment after stretching are associated with nonuniformity and
the cross-bridge model has been accepted to the point that it dispersion of sarcomere lengths (e.g., Refs. 10, 19, 45,
may be considered a true scientific paradigm. According to 56–58, 73). By using sarcomere length nonuniformity and
Kuhn (48), a scientific paradigm is expected to explain most dispersion, many results could be interpreted without alter-
but not necessarily all experimental observations in a given ing the basis of the cross-bridge model of muscle contrac-
area of investigation. In the field of muscle mechanics and tion, thereby providing a convincing and simple explanation
physiology, most studies are interpreted and explained for experimental findings that had no ready explanation on
within the framework of the cross-bridge model. the molecular level. However, there is mounting evidence
Abbott and Aubert (1) observed that the steady-state that sarcomere length nonuniformities alone cannot explain
isometric force after active shortening and active stretching force depression after shortening and force enhancement
of muscles is lower and higher, respectively, than the purely after stretch (28, 32, 61, 63, 64). Furthermore, hypotheses
isometric force at the corresponding lengths. These results based on novel findings have been proposed to explain
have been observed consistently for over 50 years in a history-dependent properties of muscle contraction (5, 32,
variety of experimental preparations (e.g., Refs. 19, 21, 30, 34).
50). This history dependence of force production is typically The purpose of this review is to present key observations
not accounted for in the mathematical formulation of the associated with force depression after shortening and force
cross-bridge model of muscle contraction (38, 41) and enhancement after stretch, to describe the main hypotheses
that have been proposed to explain these history-dependent
phenomena (including the sarcomere length nonuniformity
Address for reprint requests and other correspondence: W. Herzog, Human
Performance Laboratory, Faculty of Kinesiology, Univ. of Calgary, 2500 Univer- hypothesis), and to critically interpret the experimental
sity Dr., Calgary, AB, Canada T2N 1N4 (E-mail: walter@kin.ucalgary.ca). evidence.
http://www.jap.org 8750-7587/04 $5.00 Copyright © 2004 the American Physiological Society 419
Invited Review
420 HISTORY DEPENDENCE OF MUSCLE CONTRACTION

steady-state value within a few seconds (19, 30, 33, 58). This
steady-state force is lower than the purely isometric force
obtained at the corresponding final length.
The amount of force depression has been found to increase
with increasing amplitudes of shortening (1, 30, 34, 55, 58),
decreasing speeds of shortening (1, 13, 30, 34, 58), and
increasing forces for constant speeds during the shortening
phase (30). Force depression after shortening appears largely
unaffected by previous muscle stretch (31). Absolute force
depression in human muscles increases with increasing activa-
tion (13).
Mechanisms of Force Depression After Shortening
There are a number of hypotheses that have been proposed
in the literature to explain force depression. The following
hypotheses are the most prominent in our view: 1) sarcomere
Fig. 1. Force depression (FD) after shortening of a single fiber from the
lumbrical muscle of frog. In the length traces, 1.0 corresponds to the optimal length nonuniformity (19, 45, 58), 2) accumulation of fatigue
length for force production (Lo). Starting from a length of 20% greater than Lo, products (28), and 3) stress-induced inhibition of cross-bridge
the fiber was shortened by 10% fiber length along the descending limb of the attachment (55).
force-length relationship, at a speed of 40% fiber length/s. An isometric Sarcomere length nonuniformity hypothesis. The sarcomere

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reference contraction performed at the corresponding final length (Lf) is also
shown.
length nonuniformity hypothesis may be explained as follows
(45, 58). During shortening of a muscle (fiber) on the descend-
ing limb of the force-length relationship, sarcomeres are as-
Experimental Preparations Used to Investigate History sumed to shorten by different amounts because of instability.
Dependence of Force Production Some sarcomeres shorten a slight amount, whereas others
shorten more than average; these sarcomeres may shorten to a
Different approaches have been used to investigate the degree that places them on the ascending limb of the force-
effects of shortening and stretching on force production, and length relationship (58). This nonuniform behavior leads to a
the results vary accordingly. Researchers have used single situation in which these two groups of sarcomeres, after attain-
muscle fibers stimulated in vitro (16–21, 23, 28, 45, 64, 68, ing force equilibrium, produce tension that is smaller than that
69), whole isolated muscles stimulated in vitro (1, 5, 55) and in produced at the corresponding length obtained during an iso-
situ (9, 30–35, 58), and human muscles during electrical metric contraction in which sarcomeres are assumed to be at
stimulation (11, 13, 49, 50) or during voluntary contractions relatively uniform lengths (Fig. 2).
(49, 50, 52, 53). Although studies with single fibers provide a The sarcomere length nonuniformity hypothesis provides
controlled experimental environment and make possible the the following testable predictions: 1) force depression should
measurement and indirect regulation of sarcomere length, stud- be abolished when sarcomere lengths are kept uniform during
ies with whole muscles more closely relate to physiological and after shortening; 2) force depression should not be ob-
situations. Studies on the history dependence of force produc-
tion have been performed on the ascending limb, the plateau,
and the descending limb of the force-length relationship with
different results. In single-fiber preparations, the different parts
of the force-length relationship are typically (but not always)
defined by some average measure of sarcomere lengths (e.g.,
Refs. 19–21, 23, 45, 69), whereas in whole muscle preparations
the right edge of the plateau of the force-length relationship is
invariably defined as the length for which the muscle produces
the maximal, active isometric force (e.g., Refs. 31–34, 58).
Lengths shorter than the right edge of the plateau correspond to
the ascending limb and plateau, and lengths greater than the
right edge correspond to the descending limb of the force-
length relationship. Studies using preparations from all struc-
tural levels mentioned above and covering the various parts of
the force-length relationship will be considered in this review.
FORCE DEPRESSION AFTER MUSCLE SHORTENING

Experimental Observations
Fig. 2. Schematic representation of the sarcomere length nonuniformity hy-
An example of force depression after active muscle short- pothesis and force depression. E, Average sarcomere (fiber) length; F, different
populations of sarcomeres. During shortening of a muscle fiber (from A to B),
ening from experiments on a single muscle fiber is shown in some sarcomeres shorten by a small amount (C), whereas other sarcomeres
Fig. 1. During shortening, force rapidly decreases, and once shorten more than average (D). At equilibrium, total force is smaller than the
shortening is completed, force recovers and attains a new isometric force at the corresponding final length, generating FD.

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Invited Review
HISTORY DEPENDENCE OF MUSCLE CONTRACTION 421
served on the stable ascending limb of the force-length rela- associated with a decrease in the proportion of attached cross
tionship, because large sarcomere length nonuniformities are bridges.
not supposed to happen in this region; and 3) force depression Summarizing, some of the specific predictions arising from
should be associated with a slight increase in stiffness, because the sarcomere length nonuniformity theory are not always
after muscle (fiber) shortening some sarcomeres are assumed to satisfied in experimental studies, and, therefore, it seems un-
be on the ascending limb (or plateau) of the force-length likely that it can account for the experimentally observed force
relationship (58). depression after active muscle shortening.
Regarding prediction 1, Edman et al. (19) investigated force Accumulation of fatigue products hypothesis. Granzier and
depression with and without control of sarcomere length, by Pollack (28) suggested that an increase in protons (H⫹) and
using the segment length clamping technique (27). Force inorganic phosphate (Pi) resulting from shortening could be
depression was observed when sarcomere lengths were not responsible for force depression. It has been shown that an
controlled, but force depression was eliminated when sarco- accumulation of H⫹ and Pi during repetitive stimulation causes
mere lengths were kept uniform, suggesting that force depres- muscle fatigue (77, 78). ATP consumption increases steeply
sion was associated with the development of sarcomere length with the amount of work, consequently increasing H⫹ and Pi
nonuniformity. However, Granzier and Pollack (28) performed (79); therefore, one might expect a great increase in H⫹ and Pi
essentially the same experiments as Edman et al. (19) but when mechanical work is performed during shortening com-
observed opposite results, reaching opposite conclusions. They pared with an isometric contraction. Because H⫹ and Pi accu-
found that force depression was similar in single fibers under- mulations cannot be removed quickly (⬍1 s), but rather take
going active shortening with and without segment length con- minutes to regain resting levels, this hypothesis allows for the
trol, therefore concluding that force depression occurred even following testable predictions: 1) force depression should be

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in the absence of sarcomere length nonuniformities. Naturally, long lasting, and 2) force depression should not be abolished
Granzier and Pollack (28) may have been unable to detect by short deactivation of the muscle.
small sarcomere length nonuniformities in their system and so It has been shown repeatedly that force depression is long
may have missed the positive result observed by Edman et al. lasting (1, 28, 30, 33, 34, 45, 58). However, several studies
(19). However, for lack of further evidence, the results of these have shown that sufficiently long (⬃0.5–1.0 s) periods of force
two studies remain inconclusive. release produced by deactivation of muscles abolishes force
Regarding prediction 2, small levels of force depression depression instantaneously (1, 30, 34, 45, 58), suggesting that
have been observed on the ascending limb of the force-length this hypothesis is not correct.
relationship in different preparations (13, 28, 30, 33). Regard- Stress-induced inhibition of cross-bridge attachment hy-
ing prediction 3, there are few studies that investigated sys- pothesis. Maréchal and Plaghki (55) suggested that force de-
tematically the relationship between force depression and stiff- pression may be related to a stress-induced inhibition of cross-
ness. Interpretation of these studies is complicated by the fact bridge attachments in the myofilament overlap zone that is
that fiber or muscle stiffness is not linearly related to the newly formed during shortening. When muscle is activated,
proportion of attached cross bridges, because of the well- stress causes a small elongation of the thin and thick filaments
known compliance of the myofilaments and other structures (thick and thin filaments are slightly compliant within the
that influence fiber and muscle stiffness measurements. Nev- physiological load range) (26, 44, 47, 59, 76), possibly result-
ertheless, Sugi and Tsuchiya (69) observed that force depres- ing in angular distortions of the myosin binding sites (12). The
sion is associated with a decreased stiffness after shortening in greater the stress during activation, the greater the angular
single fibers, compared with the stiffness obtained during distortions that may cause inhibition of cross-bridge attach-
isometric contractions at the corresponding final length. Sim- ments. When the muscle is then shortened, but the stress in the
ilar results were observed by Lee and Herzog (49) using the thin filaments is maintained, the probability of cross-bridge
adductor pollicis muscle stimulated artificially. These two attachment in the newly formed overlap zone may be reduced
results suggest, but do not prove, that force depression may be (Fig. 3).

Fig. 3. Schematic representation of the idea that FD is caused


by a stress-induced inhibition of cross-bridge attachment in the
overlap zone formed by muscle shortening. Imagine that the
muscle is isometrically activated at an average sarcomere length
(A). The actin filament is stretched because of its compliant
nature. While shortening to the new length (B), stretched parts
of the actin filament enter the overlap zone. It is assumed that
attachment of cross bridges to the stretched parts of actin is
inhibited in a stress-dependent way; therefore, the amount of
force and the magnitude of shortening will influence the mag-
nitude of force depression in this theory.

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Invited Review
422 HISTORY DEPENDENCE OF MUSCLE CONTRACTION

This mechanism of force depression provides the following Fig. 4. During active stretch, force rapidly increases (20, 21,
testable predictions: 1) force depression should be long lasting 23, 32, 35, 64). After the stretch is completed, force decreases
if myofilament stress is maintained but should be abolished and reaches a steady state until the end of activation (21, 23,
instantaneously on full stress release, 2) force depression 32, 35, 64). This steady-state force is higher than the purely
should be associated with a decreased stiffness, and 3) force isometric force observed at the corresponding final length.
depression should increase with increasing shortening dis- Most studies show that the amount of force enhancement
tances, and with increasing forces during shortening, and, increases with increasing amplitudes of stretch (1, 20, 21, 64)
therefore, force depression should be directly related to the and increasing fiber or sarcomere lengths (20, 21, 64) but is
mechanical work produced during shortening. independent (or nearly so) of the speed of stretch (1, 21, 64).
All these predictions have been supported by experimental Recently, it has been shown that, at long muscle lengths, force
results. Force depression is long lasting (1, 28, 30, 33, 34, 45, enhancement is accompanied by a long-lasting increase in the
58), but when the stress from muscle or fiber preparations is passive force after deactivation of the muscle or fiber (32, 35,
released for brief moments (by deactivation), such that force 50, 64, 66, 67).
will not go to zero, there is a loss of force depression that is
directly proportional to the decrease in force during stress Mechanisms of Force Enhancement After Stretch
release (34). If deactivation is long enough, so that force goes
to zero, all force depression is abolished on reactivation (1, 34). The following comprise the primary hypotheses that have
Force depression and stiffness are closely correlated; i.e., the been proposed to explain force enhancement after stretch: 1)
greater the force depression, the smaller the muscle or fiber sarcomere length nonuniformity and instability (45, 56–58), 2)
stiffness (49, 69). Finally, it has been shown that force depres- increase in the proportion of attached cross bridges (5), and 3)
engagement of a passive element (32, 35, 60).

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sion increases with the mechanical work produced during
shortening (1, 30, 33, 34, 55, 58). Sarcomere length nonuniformity and instability hypothesis.
On the basis of the evidence presented above, and until Julian and Morgan (45) observed that, during stretch of single
experiments have been conducted to disprove directly the fibers on the descending limb of the force-length relationship,
hypothesis of stress-induced cross-bridge inhibition, it should sarcomere lengths changed nonuniformly. Sarcomeres near the
be considered as a potential candidate to explain force depres- center of the fibers were observed to stretch more than average,
sion after shortening. whereas sarcomeres near the end of the fiber stretched less than
Summary. Although in some circumstances the sarcomere average, remaining almost isometric. On the basis of such
length nonuniformity theory relates well to force depression, evidence, Morgan (57) suggested that most active force after
specific predictions from the hypothesis have been rejected in stretch is produced by the sarcomeres that did not stretch
different experiments. There is agreement that force depression is significantly, whereas the sarcomeres that were stretched to a
1) directly associated with a decrease in stiffness (49, 69) and 2) great extent would quickly reach a length at which myofila-
directly related to the magnitude of mechanical work produced ment overlap was lost. At this point sarcomeres would “pop”
during the shortening phase (34). If we assume that stiffness from (57) and be supported entirely by passive elements. The final
non-cross-bridge-related structures is constant, and that cross- force produced by these two populations of sarcomeres would
bridge attachments along the myofilaments are random for the be greater than the force produced during isometric contrac-
isometric reference and the force-depression states, then changes tions at the corresponding final length, achieved with a rela-
in stiffness reflect changes in the proportion of attached cross tively uniform distribution of sarcomere lengths (Fig. 5).
bridges (25), albeit not in a linear proportional way. Therefore, it
appears that force depression is caused by a decrease in the
proportion of attached cross bridges and not by a decrease in the
average force per cross bridge.
If so, the question arises: How does the proportion of
attached cross bridges decrease with the magnitude and force
during shortening? One possibility is that there is a stress-
induced inhibition of cross-bridge attachment in the myofila-
ment overlap zone that is newly formed during active muscle
shortening, as proposed by Maréchal and Plaghki (55). When
stress is released completely from a muscle or fiber, force
depression is abolished instantaneously (1, 34), and when
stress is released incompletely, force depression decreases with
increasing amounts of stress release (34). The detailed mech-
anism of force depression caused by a shortening-induced
decrease in the proportion of attached cross bridges is not
known and will require further research.
FORCE ENHANCEMENT AFTER MUSCLE STRETCH Fig. 4. Force enhancement (FE) after stretch of a single muscle fiber isolated
from the lumbrical muscle of frog. In the length traces, 1.0 corresponds to Lo.
Experimental Observations Starting at a length of 5% greater than Lo, the fiber was stretched by 15% of
the fiber length along the descending limb of the force-length relationship, at
Typical tracings of force enhancement after active stretch in a speed of 40% fiber length/s. Isometric contractions, performed at Lo and at
experiments conducted with single muscle fibers are shown in the corresponding initial length (Li) and Lf, are also shown.

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Invited Review
HISTORY DEPENDENCE OF MUSCLE CONTRACTION 423

Fig. 6. FE after stretch along the ascending limb of the force-length relation-
Fig. 5. Schematic representation of the sarcomere length nonuniformity and
ship of a single fiber from the lumbrical muscle of frog. In the length traces,
instability hypothesis for force enhancement. E, Average sarcomere (fiber)
1.0 corresponds to the Lo. Starting at a length of 20% below Lo, the fiber was
length; F, different populations of sarcomeres. During stretch of a muscle fiber
stretched by 10% of the fiber length, at a velocity of 40% fiber length/s. The
(from A to B), some sarcomeres are stretched by a small amount (C), whereas
isometric contraction performed at the corresponding Lf is also shown.
other sarcomeres are stretched more than average (D). The overstretched

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sarcomeres will eventually “pop” and are supported by passive force exclu-
sively (E). At equilibrium, total force is greater than the isometric force at the
corresponding Lf, generating FE. of the force-length relationship in experiments conducted with
single fibers from frog (61, 68) (Fig. 6), the cat soleus (32), the
Studies using electron microscopy on single fibers that were human adductor pollicis (14, 50), and the human dorsal inter-
fixed after an active stretch strengthen the sarcomere length osseus (11).
nonuniformity theory (10, 73). In these studies, some half- We performed a series of experiments with single muscle
sarcomeres were observed to elongate significantly more than fibers aimed at testing the prediction that force after stretch
the average half-sarcomere length, whereas some half-sarco- could not be greater than the isometric force produced on the
meres remained shorter than the average. plateau of the force-length relationship. When stretch was
The development of sarcomere length nonuniformity, and initiated at a length slightly longer than optimal length (the
the associated popping of sarcomeres after stretch, is intimately length at which active isometric force is greatest), and given
associated with the idea of sarcomere instability on the de- the right stretch conditions (amplitude, speed), the steady-state
scending limb of the force-length relationship (56–58). The isometric force after stretch exceeded the maximal isometric
notion of instability, as introduced by Hill (36), was based on force produced at optimal length (64) (Fig. 4). This result was
the negative slope of the descending limb of the force-length confirmed statistically in a study with 28 separate fiber prep-
relationship. However, force-length relationships are deter- arations (Fig. 7). A steady-state force enhancement above the
mined from isolated isometric contractions (22, 27, 74, 75), plateau of the force-length relationship cannot be caused by
and it is not correct to infer dynamic instability from static nonuniform sarcomere lengths alone.
STUDIES ON THE MYOFIBRIL LEVEL. Recently, our laboratory
observations. In fact, there is theoretical (2, 3) and experimen-
tal (4, 15, 64, 66, 67, 74) evidence suggesting that skeletal performed a series of active stretch experiments with isolated
muscle is stable on the descending limb of the force-length myofibrils, a preparation in which all sarcomeres (typically
relationship.
The sarcomere length nonuniformity hypothesis allows for
the following testable predictions: 1) force enhancement
should be abolished when sarcomere lengths are kept uniform
during and after stretch, 2) force enhancement should not be
observed on the stable ascending limb of the force-length
relationship, and 3) the steady-state isometric force after
stretch should not be greater than the isometric force at optimal
length.
Edman et al. (21) found that force enhancement was pro-
duced not only by a fixed-end muscle fiber but also by
individual “clamped” segments of the fiber containing uniform
sarcomere lengths. In fact, investigators have failed to find
large sarcomere length (37) or fiber segment length (21, 69)
nonuniformities after stretch. Therefore, it appears that force
enhancement is possible in the absence of gross sarcomere Fig. 7. Steady-state force-length relationship (F) and the steady-state forces
obtained after active stretches of different amplitudes starting at 5% (‚), 10%
length nonuniformity. (■), and 15% ({) above Lo (1.0 on the length axis). Forces were normalized
Studies performed in different laboratories have shown a relative to the maximal isometric force. Note that, for several conditions, the
small but consistent force enhancement on the ascending limb steady-state force after active stretch is greater than the isometric force at Lo.

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Invited Review
424 HISTORY DEPENDENCE OF MUSCLE CONTRACTION

attachment sites, thereby potentially increasing the probability


of myosin-actin attachments (71, 72). If stretch induces an
increase in myosin phosphorylation, it may produce the ob-
served force enhancement. Because the rate constant for de-
phosphorylation of the light chains is very slow (70), myosin
would likely remain phosphorylated for a long time after
stretch, thus producing a long-lasting force enhancement. For
this mechanism to work, either some biochemical step along
the myosin phosphorylation path would have to be affected by
active stretch (e.g., the activity of myosin light chain kinase or
phosphatase), or, alternatively, phosphorylation would have to
be upregulated by stretch per se. There is no evidence support-
ing and/or rejecting either possibility.
There is no conclusive evidence to reject the hypothesis that
Fig. 8. Length-time histories of individual sarcomeres of a single activated force enhancement is associated with an increase in the pro-
myofibril during an isometric-stretch-isometric test. The initial average sarco- portion of attached cross bridges after stretch. It remains a
mere length was 2.38 ␮m, and the average sarcomere length after stretch was potential candidate, but additional experiments have to be
2.70 ␮m. Velocity of stretch: 107.5 nm/s. conducted to clarify the differences in the results regarding
stiffness in the enhanced-force state.
7–30) are arranged in series and can be tracked during activa- Alternatively, force enhancement could be accomplished if

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tion and stretch (63). On activation on the descending limb of the average force were increased in cross bridges after stretch.
the force-length relationship, sarcomere lengths along the myo- If, during stretch, cross bridges were brought to a state that
fibril were nonuniform (Fig. 8). During stretch of the myofibril, facilitates force production, and, furthermore, if they were to
all sarcomeres were elongated, albeit by different amounts. stay in that state for subsequent cross-bridge cycles, then a
Despite length differences after the stretch, sarcomeres re- change in cross-bridge force could cause the observed force
mained at a constant length during the isometric phase after enhancement. However, there is no direct evidence supporting
myofibril stretching; i.e., they were perfectly stable (63). this idea.
Therefore, force enhancement of isolated myofibrils occurred Engagement of a passive-element hypothesis. It has been
in the absence of sarcomere length instability. suggested that force enhancement may be associated with the
The experimental evidence from studies performed on dif- engagement of a passive element on activation and the exten-
ferent structural levels contradicts some of the major predic- sion of this passive element during active stretch (32, 35, 60).
tions arising from the sarcomere instability and sarcomere This mechanism has been used in models aimed at capturing
length nonuniformity hypothesis. Although sarcomeres on the the history-dependent effects of dynamic muscle contraction
descending limb of the force-length relationship of myofibrils (24), and furthermore it provides the following testable predic-
were found to be nonuniform on activation and stretch, they tions: 1) force enhancement should be associated with an
seemed to be perfectly stable. Therefore, sarcomere instability increase in the force produced by passive elements after active
and sarcomere length nonuniformity do not appear to be the stretch, and 2) shortening introduced before a given amount of
sole cause of the force enhancement observed experimentally. stretching should decrease force enhancement in a dose-depen-
Increase in the number of attached cross bridges hypothesis. dent manner, because the passive element would be shortened
Force enhancement can be accomplished if, after stretch, there
is an increase in the proportion of cross bridges attached to
actin (5, 29). If this hypothesis is correct, force enhancement
should be accompanied by an increase in muscle or fiber
stiffness.
Experiments in which muscle or fiber stiffness was mea-
sured in the force-enhanced state as well as in the isometric
reference state are inconclusive. In some experiments per-
formed with single fibers, stiffness in the force-enhanced state
was found to be the same as that measured during the corre-
sponding isometric reference contractions (45, 69). However,
others have reported an increase in stiffness in the steady-state
force-enhanced state in cat soleus (31).
Assuming that cross-bridge dynamics play a role in force
enhancement, two hypotheses have been suggested to explain
how the proportion of attached cross bridges may be increased Fig. 9. FE in a single muscle fiber isolated from the lumbrical muscle of frog.
by active stretch: a reorientation of thin filaments to a position In the length traces, 1.0 corresponds to Lo. Starting at a length of 5% greater
closer to the thick filaments, which would increase the proba- than Lo, the fiber was stretched 15% along the descending limb of the
bility of cross-bridge attachment (5), and phosphorylation of force-length relationship, at a speed of 40% fiber length/s. A passive stretch
and an isometric contraction performed at the corresponding Lf are also shown.
the regulatory light chains of myosin (18). After the active stretch, force is greater than the isometric force recorded at Lf.
Myosin light chain phosphorylation is believed to move the There is also a passive force enhancement (PFE) after the active but not the
cross bridges toward the thin filament (54), closer to actin passive stretch.

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Invited Review
HISTORY DEPENDENCE OF MUSCLE CONTRACTION 425
before being stretched and elongation from its initial length associated with an increase in the proportion of attached cross
would be diminished compared with the case in which stretch- bridges, rather than an increase in average force per cross
ing was not preceded by shortening. bridge. However, absolute proof to support this hypothesis is
In a series of recent studies, it has been shown that force still lacking. The passive mechanism plays a role only when
enhancement is accompanied by an increase in the passive the stretch is initiated at long sarcomere (fiber) lengths and
force after active, but not passive, muscle stretch (32, 35, 50, appears to be associated with a structure that is engaged at the
64, 67) (Fig. 9). We refer to this phenomenon as “passive force onset of muscle or fiber activation.
enhancement.” Studies performed in our laboratory have
shown that passive force enhancement is long lasting (⬎25 s) CONCLUSIONS
(35), increases with stretch magnitude and initial muscle
length, but is independent of the speed of stretch (32, 35, 50). Force enhancement and force depression may be partially
However, passive force enhancement only occurs at long associated with nonuniformity of sarcomere lengths that de-
muscle or fiber length at which passive force is naturally velop during active shortening and stretch, but sarcomere
occurring. length nonuniformity seems insufficient to explain the history
If a passive element is engaged on activation, and stretching dependence of force production on its own. On the basis of a
this passive element is responsible for part of force enhance- review of the literature, and some new evidence, we suggest
ment, then shortening the passive element before stretch should that the steady-state force depression after active muscle short-
decrease the level of the total and the passive force enhance- ening is associated with a stress-induced inhibition of cross-
ment. We observed a decrease in total (31, 32, 35, 51, 62) and bridge attachment in the myofilament overlap zone that is
passive (32, 35, 62) force enhancement that was directly newly formed during shortening and that force enhancement
after active muscle stretch has two components: an active

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related to the amplitude of shortening preceding the stretch.
There are two independent observations that are consistent component, likely related to an increase in the proportion of
with the idea that a passive element may be engaged on attached cross bridges, and a passive component, possibly
activation and may contribute to the total force enhancement. related to the molecular spring titin.
Bagni and colleagues (6, 7) showed that, on activation of
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