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palaeointensity database is still much too
incomplete to test further any long-term
evolution in the geomagnetic moment.
The second possibility implies the exis-
tence of large supercontinents and their
migration towards low latitudes in response
to geoid anomalies, which could induce
tumbling of the Earth with respect to the
rotation axis. The authors mention the
Rodinia supercontinent as a candidate
because it was assembled in the late Precam-
brian and is supposed to have broken up
between 750 and 600 Myr. They also men-
tion Pangaea, which was assembled during
the Palaeozoic. It would thus be interesting
to detect any relationship between the break-
up of these supercontinents and inclination
anomalies that would reflect a change in the
geoid linked to mass redistribution.
Kent and Smethurst have raised some fas-
cinating issues about the early generation of
the geomagnetic field and about the possible
influences of the mantle on the field. This is a
Muscle
Support for the lever arm
A. F. Huxley
n pages 380 and 383 of this issue,
case that is far from closed, but tantalizing
support for their analysis comes from that
small, persistent quadrupole component
evident over the past 5 Myr.
Jean-Pierre Valet and Yves Gallet are at the Institut
de Physique du Globe de Paris, 4 Place Jussieu,
75252 Paris Cedex 05, France.
e-mail: valet@ipgp.jussieu.fr
1. Kent, D. V. & Smethurst, M. A. Earth Planet. Sci. Lett. 160,
391–402 (1998).
2. Hulot, G. & LeMouël, J.-L. Phys. Earth. Planet. Inter. 82,
167–183 (1994).
3. Quidelleur, X., Valet, J.-P., Courtillot, V. & Hulot, G. Geophys.
Res. Lett. 21, 1639–1642 (1994).
4. Johnson, C. L. & Constable, C. G. Geophys. J. Int. 122, 489–519
(1995).
5. Johnson, C. L. & Constable, C. G. Geophys. J. Int. 131, 643–666
(1997).
6. Carlut, J. & Courtillot, V. Geophys. J. Int. 134, 527–544 (1998).
7. Evans, M. E. Nature 262, 676–677 (1976).
8. Piper, J. D. A. & Grant, S. Phys. Earth. Planet. Inter. 55, 37–53
(1989).
9. McElhinny, M. W. & Lock, J. Surv. Geophys. 17, 557–591 (1996).
10. Stevenson, D. J., Spohn, T. & Schubert, G. Icarus 54, 466–489
(1983).
11. Labrosse, S., Poirier, J.-P. & LeMouël, J.-L. Phys. Earth Planet.
Inter. 99, 1–17 (1997).
detach. Attachment ends when a molecule of
X-ray diffraction and electron microscopy4,
suggested that the cross-bridge does not tilt
as a whole but that part of the myosin head
(called the ‘catalytic domain’ because it con-
tains a cleft into which ATP or ADP fits) is
rigidly attached to the actin filament and that
the part which acts as a lever is hinged to this
domain. Although that report indicated that
the amount of relative movement between
the filaments generated by a working stroke
8
would be only about 6 nm, too little to
account for the responses of intact muscle
fibres to sudden shortening steps5, subse-
quent X-ray analyses of crystals of myosin
fragments6,7 indicate a stroke of 10–12 nm.
Together with about 2 nm contributed by the
compliance of the filaments, this would
explain the 13 nm taken up during the first
few milliseconds after a quick release from
isometric contraction5.
Suzuki et al.1 describe experiments by
fluorescence resonance energy transfer
(FRET). Two fluorescent molecules are
attached to different points on myosin, and
the one working at the shorter wavelength
(the donor) is excited by light. The energy of
this excited state may transfer to the other
(the acceptor), which then emits a photon at
its fluorescence wavelength. The extent of
this energy transfer varies inversely with the
sixth power of the distance between the two

O Suzuki et al.1 and Dobbie et al.2

describe investigations which sup-
port current ideas on the way in which
ATP binds to the myosin head. This ATP is
hydrolysed during the next cycle in steps,
some of which are coupled to conformation-
fluorophores and so is a sensitive indicator of
their separation.
Suzuki et al. used a myosin fragment con-
changes in the cross-bridges between the al changes in which the cross-bridge tilts, sisting of the catalytic domain together with
myosin and actin filaments of muscle gen- stretching an elastic component and thus the presumed hinge and the beginning of the
erate force or shortening. raising the tension. lever. The two fluorophores were attached on
Length changes in muscle take place by The only attempt so far at a detailed either side of the hinge, and the extent of
relative sliding of two overlapping sets of calculation of the molecular forces between energy transfer was measured without ATP
filaments, composed respectively of myosin myosin and actin3 suggested that there is a (end of the working stroke). On addition of
and actin. Tension is generated in the overlap sequence of positions of decreasing potential ATP, which causes the recovery stroke, ener-
regions by cross-bridges formed by the heads energy, and that the head as a whole tilts from gy transfer was much reduced. When myosin
of myosin molecules, which attach to an each position to the next. However, the in the absence of actin binds ATP, it rapidly
adjacent actin filament, exert force and structure of the myosin head, established by undergoes an isomerization after which the
ATP is hydrolysed to ADP and inorganic
a b phosphate, both of which remain bound
until the next working stroke. It follows that
Myosin filament
Thick filament the recovery stroke, indicated by the decrease
in energy transfer, accompanies or precedes
the actual hydrolysis step.
Lever arm
The authors also measured energy trans-
Actin fer in two mutant myosins. With one of these,
filament Catalytic domain
believed to hold the myosin in the state before
the isomerization, the energy transfer was
similar to that in rigor; but with the other, the
myosin was in the post-isomerization state
Figure 1 Presumed shape changes in a representative cross-bridge. a, During active contraction at and the energy transfer was similar to that of
fixed overall length; b, during rigor. Increase of length corresponds to displacement of the myosin the normal myosin with ATP (after the recov-
filament to the left. The muscle is being subjected to a length oscillation with 3-nm peak-to-peak ery stroke). Therefore the recovery stroke
amplitude of relative sliding of filaments; the red outlines show the situation at the maximum length accompanies the isomerization — that is, not
and the black outlines at the minimum. In a, the centre of mass of the lever arm is to the left of that of hydrolysis itself but the preceding step.
the catalytic domain, so that the contour of total mass of the cross-bridge is more spread out in the Calculated distances between donor and
stretched case (red) than when shortened (black), respectively decreasing and increasing the intensity acceptor agreed with the changes expected
of the X-ray reflection corresponding to the repeat of myosin molecules along the filament. The from the presumed rotation at the hinge. But
intensity therefore fluctuates in opposite phase to the length. In b, the situation is reversed (centre of the efficiency of fluorescence energy transfer
mass of the lever arm is to the right of that of the catalytic domain) and the intensity fluctuation is in depends on the relative orientations of the
phase with length. fluorophores as well as on their separation.
NATURE | VOL 396 | 26 NOVEMBER 1998 | www.nature.com Nature © Macmillan Publishers Ltd 1998 317
news and views
These were unknown and, as is customary,
Suzuki et al. took an averaged value for their
effect on transfer efficiency. Their Fig. 4
(page 382), however, shows that they assume
a large change in the relative angular posi-
tions of the two fluorophores during the
working stroke, so the estimated distances
are subject to uncertainty.
Using a variant of FRET, Getz et al.8 also
showed that the working stroke is accompa-
nied by a conformational change. The donor
was a molecule containing a terbium atom
which is luminescent rather than fluores-
cent, making a combination that operates
over greater separations than ordinary FRET
and has other advantages9. The fragment of
myosin used included the catalytic domain
and the whole of the lever. The donor was
attached close to the tip of the lever and the
fluorescent acceptor to the catalytic domain;
actin was present so rigor attachments were
formed. On adding ATP (myosin dissociates
from actin and recovery stroke occurs), an
increase in transfer was found, although suf-
ficient change in separation between donor
and acceptor would not be expected from the
presumed recovery stroke of the lever. Getz et
al. concluded that the decrease of transfer
was the result of a change in orientation of
the acceptor, although other explanations
are possible. Their result is a timely warning
that FRET results do not unambiguously
indicate a change in separation between
donor and acceptor.
These observations1,8 confirm that a con-
formational change within the myosin mol-
ecule does accompany the working stroke,
but do not indicate its extent. The results of
Dobbie et al.2 are complementary: they pro-
vide a value for this extent without giving
further evidence for a conformational
change. An intact fibre from frog muscle was
stimulated and a small length oscillation was
imposed at a frequency (about 3 kHz) too
high for the conformational changes to fol-
low, so that the tension and length changes
were in phase. The intensity of the meridion-
al X-ray reflection corresponding to the
spacing (14.5 nm) of myosin molecules
along their filaments was also recorded and
its fluctuations were exactly in opposite
phase to the length changes. However, when
a similar experiment was done on a fibre in
rigor (that is, without ATP so that all cross-
bridges were presumably in the state corre-
sponding to the end of the stroke), the X-ray
intensity fluctuations were exactly in phase
with the length changes.
These results confirm those of Yagi et al.10
at a lower frequency (500 Hz) where phase
shifts are appreciable. They imply that the
long axis of the cross-bridge swings from one
side to the other of the perpendicular to the
fibre axis during a working stroke (Fig. 1).
This agrees with results from fluorescent
probes attached to the lever arm but con-
tradicts a conclusion11 reached (on a scallop
318
muscle) from electron-paramagnetic-reso-
nance spectra, a method that cannot distin-
guish between angles on the two sides of the
perpendicular.
Dobbie et al. explain these X-ray intensity
changes quantitatively. In their model (Fig.
3, page 385) the tip of the lever moves by
about 9 nm during the working stroke, a little
less than the 10–12 nm (suggested by X-ray
structures6,7) which matches the amount
deduced from sudden length changes (see
above). If this 9 nm turns out to be correct it
will therefore be necessary to postulate some
movement in addition to that from the swing
of the lever, perhaps from tilting of the
catalytic domain on the actin filament3 or
shortening of the connection of the myosin
head to the shaft of its filament12.
All of this is impressive support for the
lever-arm hypothesis, but many questions
remain. How many of the myosin heads are
active at any one time? Is the working stroke
a single event or does it go in two or more
steps? Answers may come from measure-
ments of the force and amount of movement
between a single myosin molecule and an
actin filament. But the time resolution of
such experiments is inferior to that of experi-
ments on whole fibres, the results are affect-
ed by compliance in the actin filaments,
and there are big discrepancies between
the results from different laboratories.
Moreover, experiments are done with
myosins from different animals, and at low
temperatures where the behaviour of the
intact muscle is unknown.
Many will echo Holmes’s remark6: “The
fact that these results fit so nicely with other
experiments supporting the lever-arm
hypothesis points to their significance”.
Perhaps so, but results that agree with
one’s preconceptions need to be scrutinized
with especial care. I readily admit that I am
inclined to accept results that fit with a work-
ing stroke of at least 10 nm suggested long
ago by experiments on living muscle5, rather
than values in the 4–6 nm range that were
widely accepted a year ago13.
A. F. Huxley is at Trinity College, Cambridge
CB2 1TQ, UK.
1. Suzuki, Y., Yasunaga, T., Ohkura, R., Wakabayashi, T. & Sutoh,
K. Nature 396, 380–383 (1998).
2. Dobbie, I. et al. Nature 396, 383–387 (1998).
3. Diaz Baños, F. G., Bordas, J., Lowy, J. & Svensson, A. Biophys. J.
71, 576–589 (1996).
4. Rayment, I. et al. Science 261, 58–65 (1993).
5. Ford, L. E., Huxley, A. F. & Simmons, R. M. J. Physiol. 269,
441–515 (1977).
6. Holmes, K. C. Curr. Biol. 7, R112–R118 (1997).
7. Dominguez, R., Freyzon, Y., Trybus, K. M. & Cohen, C. Cell 94,
559–571 (1998).
8. Getz, E. B., Cooke, R. & Selvin, P. R. Biophys. J. 74, 2451–2458
(1998).
9. Selvin, P. R. & Hearst, J. E. Proc. Natl Acad. Sci. USA 91,
10024–10028 (1994).
10. Yagi, N. et al. J. Synch. Rad. 3, 305–312 (1996).
11. Baker, J. E., Brust-Mascher, I., Ramachandran, S., LaConte,
L. E. W. & Thomas, D. D. Proc. Natl Acad. Sci. USA 95,
2944–2949 (1998).
12. Harrington, W. F. Proc. Natl Acad. Sci. USA 68, 685–689 (1971).
13. Howard, J. Nature 389, 561–567 (1997).
Nature © Macmillan Publishers Ltd 1998
Daedalus
Fat is a feminist issue
Fat causes a multitude of miseries these
days, mainly to women. Emaciation is
intensely fashionable. The sub-text of this
fashion, says Daedalus, is sexual, but not
in the obvious way. Many cultures
consider obesity to be sexy; George Orwell
8
commented on the rotundity of the
Englishman’s secret ideal. This makes
good biological sense. Fat is itself a source
of oestrogen, so fat women are likely to be
sexually enthusiastic — a fact celebrated
by a famous English cartoon duo.
Conversely, thin women should have a
weaker sexual drive. Anorexic women
often even cease to menstruate.
So Daedalus reckons that fashionable
slimness is really about power. A slim
woman hopes to arouse strong desire in
the opposite sex, while being immune to it
herself — a position of great power. The
age-old sex war, augmented by the modern
feminist battle, therefore decrees that
slimness should be fashionable.
This unstated realpolitik of modern
fashion leaves fat women in a sorry plight.
For not only does fat release sex hormones;
sex hormones encourage fat to accumulate,
in its usual sites around the female frame.
By positive feedback, a fat woman may get
ever fatter, more sexually needy, but less
fashionably desirable. Meanwhile her slim
sisters, sexually switched off by their
emaciation, can denounce men for
harassing them with unwanted attentions.
Daedalus wants to break this vicious
cycle. Many chemicals said to damage
animal reproduction (such as DDT)
concentrate in body fat. So DREADCO
chemists are seeking a drug which
dissolves in the fat, but stimulates rather
than sabotages its biochemistry. It must
boost not only the production of oestrogen
(so that even women with little fat will feel
sexy) but also leptin — the feedback-
control protein which counters obesity by
damping production of further fat. Arsenic
may give a clue; in low doses it can lead
both to emaciation and hypersexuality.
The biochemical development may be
long and tortuous. But the final product
will splendidly counter the malign
influence of modern fashion. With
DREADCO’s ‘Slim and Sexy’ fat-activator,
fat women will shed their girth without
damping their ardour; slim women will no
longer sacrifice sexual feeling to fashion;
post-menopausal women building their
middle-age spread may not need HRT.
Militant feminists, of course, will find
good reasons to avoid and denounce the
product.
David Jones
NATURE | VOL 396 | 26 NOVEMBER 1998 | www.nature.com