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Am J Physiol Cell Physiol 310: C17–C18, 2016;
doi:10.1152/ajpcell.00310.2015.
Editorial Focus
More roles for the (passive) giant. Focus on “The increase in non-crossbridge forces after stretch of activated striated muscle is related to titin
isoforms”
Darren T. Hwee1 and Jeffrey R. Jasper2
1
Cytokinetics, Inc., South San Francisco, California; and 2Revolution Medicines, Inc., Redwood City, California
Address for reprint requests and other correspondence: J. R. Jasper, Revolution Medicines, Inc., 700 Saginaw Drive, Redwood City, CA 94063 (e-mail:
[email protected]).
http://www.ajpcell.org
cium-activated static tension at different sarcomere lengths in
three different muscle types (psoas, soleus, and cardiac ventricle) with distinct titin isoforms. The authors observed that
static tension was different between muscles, as fast fiber psoas
myofibrils produced more tension than slow fiber soleus myofibrils. Interestingly, cardiac myofibrils did not exhibit altered
static tension under activation and stretch. This finding contrasts the role of titin in the preload-mediated increases in
cardiac contractility described by the Frank-Starling mechanism (2). The absence of static tension was observed in parallel
with an absence of residual force enhancement and further
strengthened the case that Ca2⫹ activation of titin is responsible for both occurrences. The result also suggests that titin
isoforms correlate with the physiological working range of
specific muscles, as normal cardiac muscle is not stretched
during active contraction.
Cornachione and colleagues also performed studies to investigate the mechanism by which titin produces noncontractile force under stretching conditions. Ca2⫹ can bind to the
PEVK region of titin (8), and a prevailing proposed mechanism
suggests that Ca2⫹ binds directly to titin in an activationdependent manner, leading to increased stiffness and force. An
alternative proposed mechanism suggests a dynamic regulation
of actin-binding sites where titin binds to actin in an activationand force-dependent manner that shortens its free length and
increases stiffness (5, 9). In this current study, the authors
demonstrated that titin is modulated by Ca2⫹ ions, and the
difference in the number of PEVK segments of titin isoforms
correlated to the muscle-specific differences in static tension.
Conversely, static tension remained unchanged following actin
filament extraction by gelsolin, providing support to refute the
hypothesis that titin-actin interaction is responsible for Ca2⫹activated tension or residual force enhancement. Thus, the
Ca2⫹ dependence of the passive force-sarcomere length relationship appears to be regulated by titin stiffening and not by
titin-actin interactions.
Finally, the findings from Cornachione and colleagues support the notion that titin’s role as a force regulating protein in
skeletal muscle contraction may be more relevant under eccentric contractions. Eccentric contractions act as a normal braking mechanism in response to greater opposing forces that can
occur during daily activities and exercise. The authors put
forward an interesting perspective that increased titin stiffness
during eccentric contractions might be important for attenuating stretch-induced skeletal muscle injury. This concept agrees
with the proposal by Herzog (4) that titin protects muscles
against injuries on the descending portion of the force-length
relationship, but, as mentioned above, contrasts Herzog’s proposal that passive tension under stretching conditions occurs in
part through titin binding directly to actin. Time will tell
regarding direct titin-actin interactions, with active research
0363-6143/16 Copyright © 2016 the American Physiological Society
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AS STRIATED MUSCLES, the heart and skeletal muscle both act to
provide force and motion in animals; the heart rhythmically
contracts and produces force to pump blood into the circulation, while skeletal muscle contracts to perform a broad array
of precise and dynamic movement. The core molecular mechanism that gives rise to muscle force and movement was
described in the seminal studies of A. F. Huxley and R.
Niedergerke (6) and H. E. Huxley and J. Hanson, which
demonstrated that muscle contraction occurs through the sliding of actin filaments past myosin. A multitude of studies have
since continued to identify the force determinants and regulatory components of the striated muscle contractile machinery.
In addition to delineating the precise mechanisms by which
active muscle contraction occurs, an area not as well understood, but gaining considerable research interest, is the contribution and regulation of force from noncontractile proteins.
Titin (also known as “connectin”) is the largest known
protein in the human body. This multifunctional muscle protein
affords structural integrity and noncontractile force production.
As a structural protein, titin spans half the length of a striated
muscle sarcomere and acts to maintain thick filament alignment over a dynamic range of sarcomere lengths. Titin possesses a springlike quality that generates passive resistance and
a restoring element in response to increases in sarcomere
length. At sarcomere lengths where there is an absence of
cross-bridge interaction, titin is the primary contributor of
noncontractile muscle force. The contribution of muscle tension by titin is variable according to a number of key properties. The majority of titin’s mass consists of immunoglobulin
domains and PEVK (proline, glutamine, valine, and lysinerich) segment repeats derived from differential splicing of
isoforms. Additionally, posttranslational modifications and calcium activation can regulate the degree of titin-derived static
tension (3). The importance of titin to passive tension in
muscle is evident in developmental and disease states, where
changes in titin isoforms lead to consequential changes in
muscle elastic properties (10). Because of its dynamic function
in muscle physiology and pathophysiology, a number of recent
studies have attempted to elucidate titin’s role in the regulation
of noncontractile force.
In this issue of American Journal of Physiology-Cell Physiology, Cornachione and colleagues (1) examined the relationship between titin isoforms and non-cross-bridge-derived static
tension. The authors built an elaborate single myofibril apparatus with high spatial and time resolution to detect small
alterations in passive muscle force. The studies assessed cal-
Editorial Focus
C18
ongoing. Continued research that investigates the extent of
muscle damage in titin-mutant animals following eccentric
contractions will further help clarify the role of titin in attenuating muscle injury. Lastly, studies investigating changes in
titin stiffness and/or titin calcium sensitivity with repetitive
eccentric exercise will help address titin’s role in muscle
adaptation to physical activity.
2.
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5.
DISCLOSURES
D. T. Hwee is an employee of Cytokinetics, Inc. and J. R. Jasper is an
employee of Revolution Medicines, Inc. and also cofounder and advisor to
Altos Therapeutics, LLC.
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7.
AUTHOR CONTRIBUTIONS
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9.
REFERENCES
1. Cornachione AS, Leite F, Bagni MA, Rassier DE. The increase in
non-cross-bridge forces after stretch of activated striated muscle is
10.
AJP-Cell Physiol • doi:10.1152/ajpcell.00310.2015 • www.ajpcell.org
Downloaded from http://ajpcell.physiology.org/ by 10.220.33.2 on June 15, 2017
D.T.H. and J.R.J. drafted the manuscript; D.T.H. and J.R.J. edited and
revised manuscript; D.T.H. and J.R.J. approved final version of manuscript.
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