30 THE SCIENTIST | the-scientist.com
© IKUMI KAYAMA/STUDIO K AYA M Ain between, as demonstrated by a growing group of scientists
using our techniques.
Our most important observation is that proteins can
readily fold against a pulling force, delivering a large
amount of mechanical work that surpasses that generated
by ATP-fueled motors. From this, it is evident how titin
might operate in intact muscle tissues. Titin modules are
arranged in tandem and can number up to 100 in the elas-
tic I band region, which spans sarcomeres. Passive stretch-ing, which occurs when muscle is relaxed and elongated
during activities such as yoga, will unfold and extend titin
modules under a wide range of forces and time scales. Hold-
ing a yoga pose for long periods of time results in storage of
large amounts of potential energy in the stretched muscle
through titin unfolding.
By contrast, titin folding occurs over only a few pico-
newtons in the physiological force range. Strikingly, this range
matches the range of forces produced by active ATP-driven
myosin motors. Given how these molecules are organized in
the sarcomere, it seems likely that the activation of the ATP-
driven motors relieves the force on titin, triggering spontane-
ous titin folding. This partnership suggests that the motors act
as release latches for the elastic energy stored in titin during
animal motion. Our most recent data show that in the physio-
logical force range, the power output of disulfide-bonded titin
domains matches the power output of the myosin thick fila-
ment, suggesting that these two sources of energy combine to
deliver muscle power.For a long time, the classical sliding filament model of
muscle contraction developed in the 1950s seemed unassail-
able, and challenging this concept was deemed a fool’s errand.
Ye t this theory was developed without knowledge of the exis-
tence of the giant third filament: titin. Unsurprisingly, all the
data obtained from intact muscle fibers were assumed to orig-
inate solely from the interactions between actin and myosin.
Hence, it is long overdue to consider modifying the sliding
filament theory to incorporate these striking mechanical fea-
tures of titin, and to reexamine muscle mechanics experiments
in the light of this new theory.
It speaks volumes about the state of science today that the
muscle field has been reluctant to consider the large amount
of force-spectroscopy data pointing to a role of titin in muscle
contraction. Instead, titin has been relegated solely to the
domain of muscle elasticity, with many researchers afraid
to besmirch the purity of the standard model of ATP-driven
muscle contraction. What we now know about titin should be
sufficient to trigger a paradigm shift in our understanding of
muscle contraction. gJulio M. Fernández is a professor and principal investigator in
the Department of Biological Sciences at Columbia University.MUSCULAR DOGMA: The standard textbook model of muscle
contraction includes only two main players, the filaments actin and
myosin, which slide past each other, causing the sarcomere—the basic
unit of muscle tissue—to shorten. Driven by ATP-powered myosin
motors, sarcomere contraction causes whole muscles to shorten. In the
past 40 years, researchers have explored the role of another filament:
titin. Its emerging role in muscle function, unwinding during muscle
relaxation (above) and folding during contraction (below), suggests
that the ATP-driven motors also act as latches allowing titin to fold,
providing a powerful boost to muscle contraction.Z lineH zoneAfter more than two decades of research,
it is now clear that protein unfolding and
folding under force is prevalent in biology
and plays crucial roles in processes from
protein translation to protein degradation
and most things in between.Actin FilamentMyosin filamentMyosin filamentH zoneTitinTitinZ lineZ lineMyosin filamentActin FilamentI bandSarcomereRELAXEDCONTRACTED