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Length dependence of active force production in skeletal

muscle
D. E. Rassier, B. R. MacIntosh and W. Herzog
Journal of Applied Physiology 86:1445-1457, 1999.

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on the following topics:
Biochemistry .. Sarcomeres
Biophysics .. Muscle Contraction
Biophysics .. Myofibrils
Physiology .. Muscle Fibers
Physiology .. Cross-Bridges
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invited review
Length dependence of active force production
in skeletal muscle
D. E. RASSIER, B. R. MACINTOSH, AND W. HERZOG
Human Performance Laboratory, Faculty of Kinesiology,
The University of Calgary, Calgary, Alberta, Canada T2N 1N4

Rassier, D. E., B. R. MacIntosh, and W. Herzog. Length depen-


dence of active force production in skeletal muscle. J. Appl. Physiol. 86(5):
1445–1457, 1999.—The sliding filament and cross-bridge theories of
muscle contraction provide discrete predictions of the tetanic force-length
relationship of skeletal muscle that have been tested experimentally. The
active force generated by a maximally activated single fiber (with
sarcomere length control) is maximal when the filament overlap is
optimized and is proportionally decreased when overlap is diminished.

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The force-length relationship is a static property of skeletal muscle and,
therefore, it does not predict the consequences of dynamic contractions.
Changes in sarcomere length during muscle contraction result in modula-
tion of the active force that is not necessarily predicted by the cross-
bridge theory. The results of in vivo studies of the force-length relation-
ship suggest that muscles that operate on the ascending limb of the
force-length relationship typically function in stretch-shortening cycle
contractions, and muscles that operate on the descending limb typically
function in shorten-stretch cycle contractions. The joint moments pro-
duced by a muscle depend on the moment arm and the sarcomere length
of the muscle. Moment arm magnitude also affects the excursion (length
change) of a muscle for a given change in joint angle, and the number of
sarcomeres arranged in series within a muscle fiber determines the
sarcomere length change associated with a given excursion.
force-length relationship; sarcomere length; isometric contraction; slid-
ing filament theory; cross-bridge theory; moment-angle relationship;
force-calcium relationship

THE FACT THAT PASSIVE FORCE, peak single-twitch force, maximal contractions, the length dependence of force is
and peak tetanic isometric force depend on muscle typically referred to as the force-length relationship.
length has been well described over 100 years ago by Force-length relationships are obtained during isomet-
Blix in a series of three scientific papers (6–8). Blix ric contractions; i.e., either the total muscle length, the
performed experiments on frog striated muscles and fiber length, or the sarcomere length (depending on the
found for the adductors of the thigh and the gastrocne- preparation) is kept constant during the experiment.
mius that isometric force increased with increasing With few exceptions (28), the force values in force-
lengths, reached a plateau, and then decreased. Based length experiments are the maximal steady-state forces
on these correct observations and the available struc- that are reached during isometric contractions. Sub-
tural information, Blix (8) proposed a mechanism of maximal contractions are all contractions for which
force production and shortening that was based on the maximal activation is not achieved. For submaximal
shortening of longitudinally arranged ‘‘protein fila- contractions, we will not use the term ‘‘force-length
ments’’ (Protoplasmastäbchen or Inotagmen). relationship’’ but will talk about the length dependence
The length dependence of skeletal muscle force pro- of force production.
duction may be conveniently divided into two broad This review is divided into four parts. In the first
categories: maximal and submaximal contractions. For part, the theoretical background for the force-length
relationship is given based on the cross-bridge theory.
In the second and third parts, the force-length relation-
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
ship and the length dependence of force production are
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734 discussed for single-fiber and for entire muscle prepara-
solely to indicate this fact. tions, respectively. In the fourth part, some functional
http://www.jap.org 8750-7587/99 $5.00 Copyright r 1999 the American Physiological Society 1445
1446 INVITED REVIEW

implications of the force-length property for in vivo


force and moment production are described.
Throughout the review, length dependence of force
production refers to active force production, except
when specifically indicated. Active force is defined as
the rise in force observed on activation of a muscle and
is associated with cross-bridge interactions between
myosin and actin. This restriction to active force produc-
tion should not be interpreted as a value judgment on
the importance of active vs. passive muscular forces. It
merely reflects the interest of the authors in active
rather than passive muscle properties.
PART 1: THEORETICAL BACKGROUND OF THE
FORCE-LENGTH RELATIONSHIP

The force-length relationship of sarcomeres may be


explained, to a large degree, by the sliding filament (41,
44) and the cross-bridge theories (40, 43). The sliding
filament theory assumes that length changes in sarco-
meres, fibers, and muscles are accomplished by relative
sliding of the essentially inextensible myofilaments,

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actin and myosin, within a sarcomere (Fig. 1). [Recent
evidence suggests that actin and, possibly, the myosin
filaments are not as inextensible as originally assumed
(27, 37, 46, 52, 84); however, myofilament compliance
may safely be ignored in the following considerations].
The cross-bridge theory suggests that the relative
sliding of actin and myosin is caused by independent
force generators; i.e., the cross bridges. Of particular
importance for the derivation of the sarcomere force-
length relationship are the following assumptions un-
derlying the cross-bridge theory. Fig. 2. Force-length relationship of frog skeletal muscle sarcomere,
1) The cross bridges are uniformly distributed along as derived first by Gordon et al. (28) (top), and schematic sarcomeres
the length of the myosin filament. corresponding to crucial points (1–5) labeled on the force-length
2) The actin filament has uniformly distributed curve (bottom).
attachment sites for the cross bridges.
3) The attachment/detachment probability of a cross maximal isometric force of a sarcomere is linearly
bridge only depends on its location relative to an actin related to the amount of actin-myosin overlap (Fig. 2).
attachment site and is independent of its prior history In frog striated muscle, actin and myosin lengths are
or its neighboring cross bridges (40). ⬃0.95 and 1.6 µm, respectively; the Z-line width (Figs.
4) Each cross bridge exerts, on average, the same 1 and 2) is ⬃0.1 µm, and the central part of the myosin
amount of force as any other cross bridge. filament (⬃0.2 µm) does not contain cross bridges (45,
Cross bridges are small and have a limited attach- 85). With these geometrical assumptions, it is obvious
ment range. Therefore, cross-bridge attachments only that maximal overlap between actin and myosin occurs
occur in the actin-myosin overlap zone of a sarcomere at a sarcomere length of ⬃2.0 µm [i.e., twice the actin
(Fig. 1). Together with the assumptions underlying the length (1.9 µm) plus the Z-line width (0.1 µm)]; there-
cross-bridge theory, this limitation implies that the fore, sarcomere force should be maximal at a sarcomere
length of 2.0 µm. A reduction in actin-myosin overlap
caused by extension of the sarcomere by 0.2 µm does
not decrease the force potential, because the midzone of
the myosin filament does not contain cross bridges.
Extending the sarcomere beyond 2.2 µm is associated
with a linear decrease in the number of potential
actin-myosin interactions, and active force production
should become zero at a sarcomere length of ⬃3.6 µm
(Fig. 2) [twice the thin filament length (1.9 µm) ⫹ the
thick filament length (1.6 µm) ⫹ the width of the Z line
(0.1 µm)], where no overlap of the myofilaments occurs.
The cross-bridge theory predicts well the results of
the experimental sarcomere force-length relationship
Fig. 1. Schematic representation of a sarcomere. for the plateau region (2.0–2.2 µm) and the descending
INVITED REVIEW 1447

limb (2.2–3.6 µm). On the ascending limb of the force-


length relationship (i.e., sarcomere lengths ⬍2.0 µm),
active isometric sarcomere force decreases with decreas-
ing length (Fig. 2). There are two conceptual possibili-
ties why force decreases in this region of the force-
length relationship: 1) active force production may be
reduced and/or 2) internal forces may oppose the active
forces. Active force production may be reduced because
of an increasing lateral distance between the actin and
myosin filaments at short length effecting reduced
probability of cross-bridge interaction (26). Interfer-
ence of cross-bridge interaction may occur with double
overlap of the thin filaments (28). Also, below sarco-
mere length of 1.7 µm, proper cross-bridge attachments Fig. 4. Actual data points of a sarcomere force-length relationship
may be limited by deformation of the myosin filament. obtained around the plateau region of frog skeletal muscle. Error
Internal forces that may oppose active forces include bars indicate ⫾1 SE. [Adapted from Gordon et al. (28).]
forces associated with deforming actin and myosin
filaments. Particularly myosin deformation, which oc- theoretical plateau and descending limb region for
curs when the Z lines of the sarcomere push against the human and frog muscles is ⬃2 ⫻ (1.27 ⫺ 0.95) ⫽ 0.64
ends of the myosin filament at a sarcomere length of µm. The ascending limb region for human and cat
⬃1.7 µm, appears to cause a decrease in force (28) (Fig. sarcomeres has not been determined and cannot be

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2). Furthermore, when frog sarcomeres are shortened derived without further assumptions. Sarcomere force-
below optimal length and are not constrained, they length relationships of mammalian skeletal muscle are
tend to extend to ⬃2.1 µm (72). The magnitude of this rare; however, an excellent relationship was derived
restoring force is not known, but it presumably would experimentally by ter Keurs et al. (83) for the rat
subtract from the active force. It has been suggested extensor digitorum muscle.
that the restoring force is minimal in the sarcomere The force-length property of muscle is a static prop-
length range from 1.65 to 2.0 µm, since maximal velocity of erty; static in the sense that one experimental trial
fiber shortening is not affected (48). Last, fluid and osmotic gives one data point. This basic fact is often neglected
pressures may be elevated in shortened muscle fibers in theoretical models of muscle, presumably because
and may contribute to oppose the active sarcomere the force-length relationship is typically represented
forces, as suggested by Sato (77) and Gordon et al. (28). with continuous lines (e.g., Fig. 2) rather than by
The above theoretical relationship between sarco- isolated data points (Fig. 4) (Fig. 2; Ref. 28), and
mere length and force was derived for myofilament mathematical descriptions of the force-length relation-
lengths found in frog striated muscles. Actin filament ship are given as continuous functions (89), implying
lengths vary appreciably across species (33, 85), and that the relationship is continuous in time and length.
this variation should influence the shape of the sarco- However, this implication is not correct.
mere force-length relationship. For example, the theo- Considering the force-length relationship as a con-
retical plateau region and descending limb of cat and tinuous, dynamic property has led to the notion of
human skeletal muscles are shifted to the right of that instability in sarcomere length on the descending limb
for frog (Fig. 3). The shift corresponds to twice the of the force-length curve. The negative slope of the
difference in actin filament lengths between the spe- descending limb represents the behavior of a softening
cies. Human and frog actin filament lengths are ⬃1.27 material, an unstable behavior. However, the notion of
and 0.95 µm, respectively; therefore, the shift in the instability may be incorrect, because a fiber that short-
ens or elongates shows a positive stiffness. For ex-
ample, Edman et al. (14) showed that a fiber that is
stretched on the descending limb of the force-length
relationship will become stronger as it is stretched,
rather than weaker, as one should expect based on the
force-length relationship (Fig. 5). However, and even
more importantly, Edman et al. (14, 15) showed that
the force enhancement observed during the stretch did
not disappear, but some of the force enhancement was
maintained for a long time (4.2 s). This additional force
following the stretch did not only cause a force enhance-
ment relative to the isometric force at the stretched
length but also produced an isometric, steady-state
force following the stretch that was larger than the
isometric force preceding the stretch. This latter result,
Fig. 3. Sarcomere force-length relationship in frog, cat, and human if transferable to the sarcomere level, would ensure
skeletal muscles. unconditional stability of sarcomere length on the
1448 INVITED REVIEW

Force-length relationship. To ensure isometric condi-


tions of sarcomeres while the muscle fiber force-length
properties are studied, feedback control of sarcomere
length is necessary. This can be approximated by
control of a segment of the fiber length. Gordon et al.
(28) used segment length control in their classic study
of the force-length properties of isolated fibers of frog
skeletal muscle. These authors used a spot follower
device and servo control to maintain a constant dis-
tance between two markers on a short segment of the
muscle fiber. Even with segment length control, there is
some uncertainty that sarcomere length remains con-
stant throughout the tetanic contraction. Redistribu-
tion of sarcomere length was thought to occur after the
rapid rise of tension, and this redistribution of sarco-
mere length was coincident with a slow rise in tension
referred to as tension creep.
Gordon et al. (28) were the first to describe the
force-length properties of skeletal muscle sarcomeres.
They reported that peak active tension during the rapid
rise of tension was constant across a sarcomere length

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range from 2.0 to 2.2 µm. At progressively longer
sarcomere lengths, active tension decreased linearly,
reaching zero at 3.6 µm (Fig. 2). This segment of the
force-length relationship is referred to as the descend-
ing limb. When sarcomere length was ⬍2.0 µm, devel-
oped tension was less than the peak value, decreasing
linearly to a sarcomere length of ⬃1.7 µm and decreas-
ing more steeply at even shorter sarcomere lengths
(ascending limb). These observations are consistent
Fig. 5. Actual data of force enhancement and positive sarcomere with predictions based on the cross-bridge and sliding
stiffness on descending limb of the force-length relationship for frog filament theories of muscle contraction.
skeletal muscle. Relationship between force (stress) and sarcomere Edman and Reggiani (17) observed a force-length
length; r and the corresponding solid lines represent isometric
force-length relationship for single fibers from semitendinosus of
relationship that was slightly different from that re-
Rana temporaria. A: j and the corresponding line represent steady- ported by Gordon et al. (28). They observed a sigmoidal
state force at 4.3 s after completion of 0.2 µm/sarcomere stretches at decline in developed tension on the descending limb of
constant speed. Dashed lines connecting the isometric force-length the force-length relationship and suggested that this
curve with steady-state force values following stretch show the origin sigmoidal rather than linear decrease in force was
and the end of stretch. Note that dashed lines do not show the actual
force-length trace followed during stretch. B: stretches of varying consistent with small sarcomere length nonuniformi-
lengths (different symbols), beginning at 2 different initial lengths ties within the length-controlled segment. They argued
are illustrated. Temperature: 1.49°C, cross-sectional area of fiber: that such a distribution of sarcomere lengths might
10.312 ⫻ 10⫺3 mm2. [Adapted from Edman et al. (14, 15)]. diminish the magnitude (width) of the plateau region of
the force-length relationship and may permit some
descending limb of the force-length relationship (1, 21, force development in the fiber at a mean sarcomere
22). length that is ⬎3.6 µm.
PART 2: SINGLE-FIBER EXPERIMENTS
Although there are minor discrepancies in the re-
sults of studies that have used a segment length-
To test predictions of the cross-bridge theory associ- control approach, the general findings are the same and
ated with the force-length relationship, strict criteria they support the cross-bridge theory of muscle contrac-
must be adhered to: the sarcomere length must be tion (16, 17, 29, 31, 47).
isometric, and activation of the muscle must be maxi- Fixed-end muscle contractions. In circumstances
mal. When muscle contracts under conditions that do where sarcomere or segment length-control is not used,
not comply with these conditions, muscle length still the term ‘‘fixed-end contraction’’ is appropriate. In this
has an effect on the magnitude of the contractile type of experiment, ‘‘isometric’’ refers to the muscle
response, but the predictions of the cross-bridge theory (fiber) tendon unit, since only the distance between the
will not necessarily be confirmed. In this section, the fixed ends remains constant. In addition to changes in
force-length properties of single skeletal muscle fibers sarcomere length during the slow change in developed
are described, and the length dependence of the contrac- tension (creep), there can be rapid adjustments of
tile response is considered when these strict criteria sarcomere length due to stretching of compliant struc-
(isometric sarcomeres and maximal activation) are not tures in series with the fiber. Under these circum-
present. stances, there is still a length dependence of developed
INVITED REVIEW 1449

tension. Some investigators have reported a shape of stretched fibers, sarcomere lengths are shorter near the
the apparent force-length relationship quite similar to ends compared with the middle of fibers (9, 42, 49).
the force-length relationship described above (48, 82). During contraction at long lengths, sarcomeres situ-
However, others have reported differences in the shape ated near the ends of the fibers were found to shorten,
of the length-dependance of force in fixed-end contrac- whereas sarcomeres in central parts of the fiber were
tions, compared with the shape found with length- found to be stretched (16, 17). The important question
controlled contractions. The plateau of the relationship is, How can nonuniformity of sarcomere length permit
is more curved and extends to longer sarcomere lengths greater force development on the descending limb?
in fixed-end experiments than in length-controlled ex- Assuming that each sarcomere follows a force-length
periments. This extended plateau results in greater relationship according to the cross-bridge theory and
forces at any given average sarcomere length on the that sarcomere lengths are nonuniform, then long
descending limb than those obtained by using length- sarcomeres will be weaker than short sarcomeres on
controlled experiments (31, 82), giving a length depen- the descending limb of the force-length relationship.
dence of active force that is situated to the right, Therefore, on activation, long (weak) sarcomeres should
relative to the length-controlled force-length relation- lengthen, and short sarcomeres should shorten. Be-
ship (Fig. 6). The difference in the descending limb cause the ends of the fiber are fixed, the average
between theoretical and experimental studies has been velocity of sarcomere length change must be zero.
a focus of criticism of the sliding filament theory by Considering the simplest case (2 sarcomeres in series),
Pollack (68–70) and ter Keurs et al. (82). However, it is the velocity of lengthening of one sarcomere will be
recognized that nonuniform sarcomere lengths may equal to the velocity of shortening of the other one, and
account for this difference and it is not appropriate to the force transmitted across the sarcomeres will be

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discard the cross-bridge theory based on the results of equal. Considering that the slope of the eccentric side of
experiments with fixed-end contractions. the force-velocity relationship is steeper than that of
Hill (38) was the first to propose that, when a muscle the concentric side means that the force transmitted
is stimulated to contract at a long length, redistribution across these two sarcomeres in series will be much
of segment lengths occurs, and he suggested that this closer to the isometric force of the shorter (stronger,
redistribution was responsible for the slow phase of rise shortening) sarcomere, than to the force for the ‘‘aver-
in force tension (creep) during a tetanic contraction. age’’ isometric sarcomere length (63, 64). Therefore, the
This idea was advanced by Gordon et al. (28, 29), who force at any average sarcomere length beyond the
proposed more specifically that tension creep was caused sarcomere length of optimal overlap of the myofila-
by a redistribution of sarcomere lengths during a ments will be greater for fixed-end contractions than
tetanus, and that this redistribution would cause an the force predicted by cross-bridge theory, for that
increase in sarcomere length nonuniformity. In a series (average) sarcomere length.
of experiments, Edman and Reggiani (16, 17) provided This explanation of the enhanced force on the descend-
evidence that sarcomere length is not generally uni- ing limb of the length-tension relationship of skeletal
form along the length of an isolated muscle fiber, muscle requires that individual sarcomeres will con-
neither at rest nor during activation. At rest, in highly tinue to change length, resulting in increased inhomo-
geneity (16) and increased isometric tension during a
tetanic contraction. This increasing tension is thought
to be the tension creep that has commonly been ob-
served. It has been predicted that when individual
sarcomeres shorten to a length less than the optimum
(to the ascending limb of the force-length relationship),
they will eventually reach a length where the isometric
force of the sarcomere is equal to the force transmitted
across the sarcomeres, and shortening will stop (64).
Another potential explanation for the enhanced iso-
metric force on the descending limb exists. It is known
that stretch of a muscle fiber results in a permanent
enhancement of active force above that predicted for an
isometric contraction at the new length (14, 15) and
that shortening has the opposite effect (13). This effect
of stretch has been referred to as stretch-induced force
enhancement (14, 15). Although these force modula-
tions may also be attributed to inhomogeneity of sarco-
mere lengths (18, 47, 62), these modulations could be a
property of individual sarcomeres.
Submaximal contractions. The shape of the force-
Fig. 6. Predicted force-length relationship (plateau and linear de-
crease in active force) and representation of active force for fixed-end
length relationship and the length-dependence of force
contractions of mouse extensor digitorum longus fiber bundles (curved development in fixed-end contractions, as described
line). max, Maximum. [Adapted from Rassier (73).] above, was determined in single muscle fibers that
1450 INVITED REVIEW

were maximally activated (tetanic contractions). When troponin C. Therefore, the level of activation depends
the stimulation is at a subfusion frequency, activation on the time history of Ca2⫹ transients. However, the
is submaximal, and the shape of the length-dependence kinetics of Ca2⫹ binding to troponin C and of cross-
of force development is not the same as for maximal bridge interaction have a damping effect on the relation-
contractions (3, 71). In particular, during submaximal ship between intracellular Ca2⫹ concentration and ac-
levels of stimulation, peak active tension occurs at a tive force, since oscillations in force at a given frequency
length longer than the length associated with maximal of stimulation are smaller than oscillations in free Ca2⫹
overlap of the myofilaments (79). concentration. The force developed at a given average
During submaximal contractions, greater force is free Ca2⫹ concentration and a given magnitude of
obtained when the number of available cross bridges is myofilament overlap depends on the proportion of Ca2⫹
reduced by an increase in muscle length. This property binding sites that are occupied and on the kinetics of
of muscle appears to be associated with enhanced cross-bridge interaction. The kinetics of cross-bridge
activation at long muscle lengths and has been referred interaction can be considered, in the simplest case, to
to as length-dependent activation (16, 53, 78). The term be governed by two rate constants (f and g; the rates of
‘‘activation’’ has been used in many different ways in attachment and detachment of cross bridges, respec-
the skeletal muscle literature, for example, to indicate tively). For the case in which there is a large constant
the relative frequency of stimulation or frequency of number of identical attachment possibilities [i.e., cross
membrane action potentials of a muscle or motor nerve bridges with identical x-values (40) at each instant in
(5); to reflect the intracellular levels of free Ca2⫹ (4); or time], the proportion of attached cross bridges (n) will
to reflect the proportion of troponin C with Ca2⫹ bound be a function of time exclusively; i.e.
(2), among others. In general, this term is used to

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indicate a change of state from inactive to active and is dn
⫽ (1 ⫺ n) f (x) ⫺ ng(x)
often coupled with an implication of relative amplitude dt
(‘‘level of activation’’). For this reason, the term ‘‘muscle
activation’’ is defined here as the proportion of troponin For the specific state of dynamic equilibrium, when
C with Ca2⫹ bound. dn/dt ⫽ 0, the value for the proportion of attached cross
The isometric developed tension in a submaximally bridges, neq, becomes
activated, single skinned skeletal muscle fiber is deter- f (x)
mined by the following: average overlap of the myofila- neq ⫽
ments, free Ca2⫹ concentration, and the force-Ca2⫹ f (x) ⫹ g(x)
relationship (Fig. 7). Factors affecting Ca2⫹-binding Attempts to measure Ca2⫹ binding to troponin during
kinetics alter the proportion of troponin C that is skeletal muscle activation have failed to demonstrate a
occupied by Ca2⫹ at a given free Ca2⫹ concentration. In length dependence of Ca2⫹ affinity of troponin (25, 67,
an intact cell, the frequency and magnitude of Ca2⫹ 86, 87). Furthermore, the increase in force at long
oscillations (10) will affect the extent of Ca2⫹ binding to lengths during submaximal stimulation has been ob-
served in skinned fiber preparations (20), so it is not
dependent on an enhancement of the free Ca2⫹ concen-
tration. Furthermore, Balnave and Allen (3) have shown
that, for the mouse flexor digitorum brevis muscle,
average free Ca2⫹ concentration is independent of
length for a given low frequency of stimulation.
Studies using skinned fiber preparations have shown
that when free Ca2⫹ concentration is submaximal there
is more relative active force developed at long than at
short sarcomere lengths. This result implies that there
is a leftward shift in the force-Ca2⫹ relationship when
the muscle is stretched to lengths beyond optimum (19,
20, 59, 61, 80). This property of skeletal muscle is
illustrated in Fig. 7. The force-Ca2⫹ relationship has
been used as an indicator of Ca2⫹ sensitivity (59, 79). A
leftward shift of the force-Ca2⫹ relationship represents
increased sensitivity, and a rightward shift represents
decreased sensitivity. At long sarcomere lengths, the
Ca2⫹ sensitivity is increased, but activation is not
affected. Therefore, the increased Ca2⫹ sensitivity at
long sarcomere lengths is likely caused by changes in
cross-bridge kinetics. It is believed that changes in
Fig. 7. Force-pCa2⫹ relationships. The 2 curves represent normal intermyofilament spacing, as a consequence of changes
situation on the right and increased Ca2⫹ sensitivity (shift to left).
Curves were drawn from published values for the Hill equation
in muscle length, may be responsible for these altered
presented by Martyn et al. (58) for skinned twitch fibers of a frog cross-bridge kinetics and, therefore, length-dependent
muscle at 2.4- (right) and 3.1-(left) µm sarcomere lengths. changes in Ca2⫹ sensitivity (24, 25, 65, 67, 87).
INVITED REVIEW 1451

It has been shown that intermyofilament spacing predicted according to the cross-bridge theory. Presum-
decreases as skeletal muscle is stretched (60, 74, 75). ably, the same mechanism responsible for this shift in
Using skinned fibers of rabbit soleus, Godt and single fibers can explain this shift in whole muscles.
Maughan (26) confirmed that compression of the myo- Distribution of sarcomere lengths. When the relation-
filament lattice at short sarcomere length with high- ship between length and developed tension is assessed
molecular-weight dextran resulted in enhanced Ca2⫹ in a multicellular preparation, one must ask whether
sensitivity (leftward shift in the force-Ca2⫹ relation- the mean sarcomere length in one cell is the same as in
ship). These results have been confirmed by other an adjacent cell. Differences in mean sarcomere length
investigators (12, 81, 87). Because compression of the between adjacent fibers could occur because of different
lattice can enhance Ca2⫹ sensitivity, and the myofila- numbers of sarcomeres in series for fibers of a given
ment lattice is compressed at long lengths, it is reason- length or because of differences in the fiber-to-tendon
able to assume that lattice compression is responsible length ratio over a given length of muscle. It has been
for the length-dependent increase in Ca2⫹ sensitivity. reported that sarcomere length variation is greater in a
The specific conditions within the myofilament space bundle of fibers than in a single fiber (66). If fibers
that affect length dependence of Ca2⫹ sensitivity are within a given muscle have different average sarco-
unknown. One explanation that has been offered is that mere lengths at a given muscle length, peak force
proximity of the myofilaments enhances the probability would be reduced and the plateau would be broader,
of cross-bridge interaction (26). This enhanced probabil- compared with fibers of identical sarcomere lengths
ity would be expected to increase the rate constant for within a given muscle.
cross-bridge attachment, f(x). If rate of detachment, The distribution of sarcomere length across fibers
g(x), remains unaffected by intermyofilament spacing, appears to be greater for the rat extensor digitorum

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an increase in f(x) would effectively result in a greater longus than for the rat medial gastrocnemius muscle
number of cross bridges being engaged during a contrac- (39), which might explain the relative broadening of the
tion and thus enhance the amount of tension produced. relationship between developed force and muscle length
for the extensor digitorum longus. It has also been
found that the optimal length of individual motor units
PART 3: ISOLATED WHOLE MUSCLE
varies within a given muscle (23, 54), suggesting that,
It is difficult to use the segment or sarcomere length at a given muscle length, different motor units have
control approach to the study of the force-length proper- different mean sarcomere lengths.
ties of whole isolated or semi-isolated muscles. There-
fore, we will not discuss segment-controlled experi- PART 4: FUNCTIONAL IMPLICATIONS
ments in this section, and the results of experiments In the previous parts of this review, we were con-
with whole muscle will be described as the length- cerned with the force-length properties and the length
dependence of active force. dependence of force production in isolated skeletal
Rack and Westbury (71) found an extended plateau muscles, fibers, or sarcomeres. In reality, muscles are
in the length dependence of active force for tetanic attached (typically) to bones, and they cross one or
contractions in cat soleus muscles. The developed force more joints at which they function to produce move-
did not start to decrease significantly until a muscle ments. The forces exerted by muscles create a moment
length corresponded to an average resting sarcomere about the joint(s).
length of ⬃3.0 µm. The extended plateau of the length- When considering the force-length characteristics of
dependence of active force could be caused by elastic a muscle in its anatomic environment, two factors
elements in series with the muscle fibers that allow for should be considered when evaluating the potential of
sarcomere shortening to a length much less than the the muscle to produce movements: the moment arm of
resting sarcomere length. the muscle about the target joint and the excursion
Close (11) reported a length dependence of force in of the muscle. The moment arm of the muscle deter-
whole muscle, similar to the force-length relationship mines the moment (Mj ) produced about a joint by
observed by those using segment control in single fibers muscular contraction since
(17, 28, 31); i.e., the force decreased linearly with
decreasing filament overlap on the descending limb of Mj ⫽ r ⴛ F
the force-length relationship. Close (11) minimized the
effect of series elastic elements that may have permit- where r is the location vector from the center of the
ted better agreement between the active and passive joint to any point on the line of action of the muscle
sarcomere lengths than had been obtained by others force, F is the muscle force (vector), and ⴛ represents
(57). the vector cross product (Fig. 8A). For two-dimensional
Submaximal contractions. As in studies with single considerations, the above equation may be written in
cells, studies with whole muscles revealed that the its scalar form as
length dependence of force varies with different levels Mj ⫽ d · f
of muscle stimulation. The results of these studies
showed that the optimal length for twitch contractions where Mj is the magnitude of the moment produced by
(11, 71, 76) and submaximally activated muscle (76) the muscle about the target joint, d is the perpendicular
was shifted to longer muscle lengths than would be distance (moment arm) from the joint center to the line
1452 INVITED REVIEW

with muscle A for a given change in joint angle;


therefore, muscle B has only one-half the range of
active force production (in terms of joint angular dis-
placement) compared with muscle A (Fig. 10).
Because the moment-angle relationship of a muscle
about a joint is determined by the force-length proper-
ties of the muscle and the variable moment arm, the
following three basic scenarios relating force and mo-
ment arm to the joint moment are possible (Fig. 11): 1)
the moment arm is about constant throughout the
range of joint motion; therefore, the shape of the
moment-angle relation reflects the shape of the force-
length relation accurately (Fig. 11A); 2) the moment
arm is decreasing (increasing) as the force potential of
the muscle is increasing (decreasing); therefore, the
moment-angle relation is flattened compared with the
force-length relation (Fig. 11B); and 3) the moment arm
is increasing (decreasing) as the force potential is
increasing (decreasing), therefore the moment-angle
relation is an enhanced version of the force-length
relation (Fig. 11C). Depending on the exact relation

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between the force-length property of the muscle and
the corresponding moment arm, the joint angle of
Fig. 8. Schematic representation of a muscle and its moment arm maximal muscle force may not correspond to the joint
crossing a single joint. Illustrated in A is the force vector (F) and its angle of maximal moment.
line of action. Also shown is the location vector, r, showing the Excursion is defined as the change in length of a
distance from center of the axis of rotation to the line of action of the muscle when going through the full anatomical range
muscle. In a 2-dimensional consideration, the moment about the axis
of rotation, which is due to the muscle, is given by d · f, as shown in B.
of joint motion (i.e., longest to shortest in situ length).
See text for further description. Intuitively, one might assume that a muscle is attached
to the musculoskeletal system such that it operates
essentially at or around its optimal length (i.e., a length
of action of the muscle force, and f is the magnitude of at which it is strongest). However, this assumption is
the muscle force (Fig. 8B). not correct. Most muscles whose in situ force-length
The importance of the moment arm may be illus- properties have been determined appear to operate
trated in an example with two muscles of identical primarily on the ascending or descending limb of the
force-length properties crossing the same joint, but force-length relationship, reaching the plateau toward
their moment arms are different by a factor of two (Fig.
9). If we assume that muscle B has a moment arm twice
that of muscle A, it is obvious that muscle B can exert a
peak moment twice that of muscle A. However, the
larger moment arm of muscle B compared with A
causes a larger change in length of muscle B compared

Fig. 10. Schematic force-length relationship of muscles A and B from


Fig. 9. Although muscles A and B were assumed to have identical
physiological cross-sectional areas and fiber lengths, their moment-
joint angle relations differ substantially because of their difference in
moment arm length (see d in Fig. 8). Muscle B (with the large
moment arm) will produce a larger moment for a given muscle force
Fig. 9. Schematic representation of 2 muscles (A and B) crossing a than will muscle A; however, muscle B has a larger excursion than
single joint. Both muscles are identical in all aspects, except muscle B muscle A for a given change in joint angle; therefore, its active range
has a moment arm twice that of muscle A. of force production (b) is smaller than that of muscle A (a).
INVITED REVIEW 1453

Fig. 11. Force- (solid line) and moment- (dashed


line) joint angle (␣) relationships for a muscle with 3
different (A-C) moment arm (r)-joint angle relation-
ships.

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the end of the range of joint motion. For example, the descending limb of the force-length relationship during
cat soleus, gastrocnemius, and plantaris muscles have everyday use (56).
all been found to work primarily on the ascending limb The question that arises is, Why do different muscles
of the force-length relationship (34, 71). Similarly, occupy different parts of the force-length relationship
human gastrocnemius muscles operate primarily on in vivo? The answer to this question is not known;
the ascending limb of the force-length relationship (35). however, it appears likely that there is some connection
However, frog semitendinosus appears to occupy the between the functional demands of a muscle and the
region of the force-length relationship it occupies. For

Fig. 12. Schematic representation of a force-fiber length relationship Fig. 13. Active (a), passive (p), and total (t) force-length relationships
and a muscle undergoing a stretch-shortening (loop on left) and a for frog gastrocnemius, sartorius, and semitendinosus muscles
shortening-stretch (loop on right) cycle. [Adapted from Wilkie (88).]
1454 INVITED REVIEW

Fig. 14. Schematic representation of the in vivo force-joint angle relationships of human rectus femoris for normal
subjects (A), high-performance runners (B), and cyclists (C).

example, during everyday movement tasks, muscles Up until now, the force-length property of skeletal
undergo either a stretch-shortening or a shortening- muscle has been considered as a given, constant charac-
stretch cycle. In a stretch-shortening cycle, a muscle is teristic. However, muscles have a tremendous ability
stretched initially as it increases its force and then for adaptation. Therefore, the question arises, Do in
shortens as it decreases its force (Fig. 12). Such a vivo force-length properties adapt to changes in every-
function follows a ‘‘force vs. length’’ curve with positive day requirements, changes that might be produced, for
slope, similar to that of the ascending limb of the example, by chronic training or tendon transfer sur-

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force-length relationship. During a shortening-stretch gery?
cycle, a muscle shortens first as it develops force and In a study aimed at determining the in vivo force-
then is stretched as its force decreases. This function length properties of human rectus femoris muscles, we
follows a negative force vs. length plot, similar to the made the following observations (Fig. 14): the force-
descending limb of the force-length relationship. length curve for normal subjects was centered around
For the few muscles for which functional and in vivo optimal length (Fig. 14A) (36), whereas the force-length
force-length properties are known, it appears that curves of national caliber runners and cyclists fell on
muscles undergoing stretch-shortening cycles during the ascending and descending limb of the force-length
normal movements operate on the ascending part [cat relationship, respectively (Fig. 14, B and C) (32). Al-
and skunk triceps surae, plantaris, and human gastroc- though the sample size for the different groups was
nemius (30, 34, 35, 71)], and muscles undergoing small (n ⫽ 9, 4, and 3 for normal subjects, runners, and
shortening-stretch cycles operate on the descending cyclists, respectively), the force-length regression lines
part of the force-length relationship [frog semitendino- for the runners and cyclists were statistically (␣ ⫽ 0.05)
sus (56)]. It is also worth noting that muscles that different from zero, whereas those of the normal sub-
operate on the ascending part of the force-length rela- jects were not.
tionship tend to have a passive force that appears at There is a variety of possible explanations for why
short muscle length, whereas muscles that operate on the force-length properties for the runners were differ-
the descending part tend to have passive forces that ent in shape from those of the cyclists; the most
appear only at long muscle length (Fig. 13). appealing reason is an adaptation of the number of
sarcomeres arranged in series in the muscle fibers.
Following this argument, one would assume that the

Fig. 15. Schematic representation of 2 muscle fibers of equal length.


One fiber contains more sarcomeres in series than the other; there- Fig. 16. No. of sarcomeres arranged in series in superficial and deep
fore, its average sarcomere length is smaller than that of the fiber portions of rabbit tibialis anterior (TA) muscle. c, Control animals, no
with the fewer sarcomers. If the number of sarcomeres in the 2 fibers retinacular release; s, sham-operated animals, no retinacular re-
at a given length is sufficiently different, then one fiber might be lease; r, experimental animals, retinacular release. * Release group,
operating on the ascending limb and the other on the descending limb significantly different from control and sham-operated groups, P ⬍
of the force-length relationship. 0.01 (51).
INVITED REVIEW 1455

number of sarcomeres in series in rectus femoris muscle as well as between muscle length and joint angle. These
fibers of runners is larger than in cyclists; therefore, for nonlinearities are directly associated with the variable
a given joint configuration, the average sarcomere moment arm of the muscle force vector about the target
length of the runners would be smaller than that of the joint. Therefore, moment arm determination or, equiva-
cyclists (Fig. 15). Whether this type of adaptation really lently, the determination of the instantaneous joint
occurred in the top athletes could not be evaluated. axis and line of action of the muscle become of utmost
In an attempt to determine whether the number of importance when determining the in vivo force-length
sarcomeres arranged in series within muscle fibers properties of muscles. However, the in vivo determina-
would adapt to tendon transfer procedures, the follow- tion of these factors is often difficult and sometimes
ing study was performed (50, 51). The tendon of the impossible.
rabbit tibialis anterior was released from its retinacu-
lar constraint at the ankle. For the experimental D. E. Rassier was supported, as a graduate student, by Centro de
Aperfeicoamento de Pessoal de Ensino Superior (Brazil).
animals (retinacular release), the origin to insertion Present address of D. E. Rassier: Escola de Educacao Fisica,
distance of the tibialis anterior (and, therefore, its Laboratorio de Pesquisa do Exercicio (LAPEX), Rua Felizardo 750,
passive force) became smaller, but the moment arm Bairro Jardim Botanico, Porto Alegre (RS), Brazil.
about the ankle (and, therefore, its excursion) became Address for reprint requests and correspondence: B. R. MacIntosh,
larger than it was for the control animals (no surgery or Human Performance Laboratory, Faculty of Kinesiology, The Univer-
sity of Calgary, Calgary, AB, Canada T2N 1N4 (E-mail:
sham surgery). If active or passive forces were the brian@kin.ucalgary.ca).
primary positive modulators of the number of in series
Received 22 May 1998; accepted in final form 23 December 1998.
sarcomeres, one would expect to see a decrease in the
number of sarcomeres in the experimental compared

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