Académique Documents
Professionnel Documents
Culture Documents
1957 Model
J. Jeremy Rice
IBM T.J. Watson Research Center, P.O. Box 218,
Yorktown Heights, NY 10598
johnrice@us.ibm.com
914-945-3728
Last slides from last lecture
Solved problem from McMahon, p. 21
Solved problem from McMahon
Solved problem from McMahon
(Assumes not less than slack length)
the derivative of
^
Solved problem from McMahon
Exponential fall
has terms with
exp(-(t-t
init
)/t)
where t = B/K
Exponential rise
has terms with
(1-exp(-(t-t
init
)/t))
where t = B/K
Method 2
0 at t 0 T
init init
= =
T
0
0
t = 0 C C +A
2C +A t -> infinity
Assume output of active element is T
0
for infinitely long time
) e 1 ( T ) C ( T
C
B
K
0
=
0
T T =
t t / ) t t (
init
/ ) t t (
init init
e T ) e 1 ( T ) t ( T
+ =
where t = B/K
Therefore and ) e 1 ( T ) t ( T
t
B
K
0
=
Method 2
T
0
0
t = 0 C C +A
2C +A t -> infinity
) A (
B
K
e ) C ( T ) A C ( T
= +
t t / ) t t (
init
/ ) t t (
init init
e T ) e 1 ( T ) t ( T
+ = where t = B/K
Therefore
C at t ) C ( T T
init init
= =
Now repeat process but move forward in time so t
init
= C
0 T =
and
Assume output of active element is 0 for infinitely long
) C ( T
t / ) C t (
e ) C ( T ) t ( T
=
and
) A C ( T +
Note that time constant will change if
more elastic elements are added
For example, if K
PE
and K
SE
are above slack length and
total length x is fixed, then t = B/(K
PE
+ K
SE
)
Warning: K
PE
and K
SE
are nonlinear elements
Answer to part b
= 1 when C (A can be anything)
t = 0 C C +A
2C +A
T
0
0
t = 0 C C +A
2C +A
= 1 when A (C can be anything)
t = 0 C
C +A 2C +A
= 2 when A and C 0
T
0
0
T
0
0
x =(1+e
K( A+C)/B
)
= 2 when C 0 and A 0
Goals
Force-Velocity relations
Evidence for sliding filament theory
Derivation of Huxley '57 Model
Force-Velocity Relations
Experimental setup
Force-velocity relations
Force-velocity relations
Simple models fail to
explain the downward
droop in force-velocity
relations
Except for extreme cases maximum
shortening velocity is constant (V
o
)
Factors affecting the measurement of V
o
.
A) time of release. V
o
(open circles) is independent of
time when twitch force (solid line) is >70% of F
0
.
B) sarcomere length on F
o
. Active and passive
force development as function of sarcomere length
C) sarcomere length on V
o
. Sarcomere length does
not affect V
o
above slack length (~1.90 m).
D) speed of release. Increasing the rate of muscle
release does not affect sarcomere shortening velocity
over a wide range. This demonstrates that the actual
maximal shortening velocity of the sarcomeres is rate
limiting, and thus allows for the direct measurement of
V
o
.
* Do not worry about length and activation state just think of
action of crossbridges as setting force-velocity relationship
More XB are attached as
velocity decreases
* But this is just part of the story - extension changes also
Peak power occurs midway in
F-V relations
Evidence for sliding
filament theory
What was "known" - evidence for
sliding filaments and cycling force
generators
The smallest contractile unit is the sarcomere
The sarcomere is composed of actin & myosin
Filaments slide but do not change length
Force proportional to degree of overlap
The maximum sarcomere length for contractile force
development is ~3.6 m - above this length no active force
is generated
Maximum unloaded velocity is independent of SL
Except for extreme cases maximum
shortening velocity is constant (V
o
)
Factors affecting the measurement of V
o
.
A) time of release. V
o
(open circles) is independent of
time when twitch force (solid line) is >70% of F
0
.
B) sarcomere length on F
o
. Active and passive
force development as function of sarcomere length
C) sarcomere length on V
o
. Sarcomere length does
not affect V
o
above slack length (~1.90 m).
D) speed of release. Increasing the rate of muscle
release does not affect sarcomere shortening velocity
over a wide range. This demonstrates that the actual
maximal shortening velocity of the sarcomeres is rate
limiting, and thus allows for the direct measurement of
V
o
.
* Do not worry about length and activation state just think of
action of crossbridges as setting force-velocity relationship
Alternative theory proposed opposite
charges exist in thick and thin filament
Contraction from electrostatic attraction
Hard to reconcile with maximum velocity being
independent of sarcomere length
Derivation of Huxley '57
Model
Review three key concepts from basic probability:
1. Probability Density Functions
Example:
Consider an electron of a hydrogen atom. One could
draw an approximate probability density function (p.d.f.)
for its location in terms of distance from the nucleus = r.
Let h(r) be the function below that defines this p.d.f.
r
proton
r=0 r
h(r)
electron
The way to interpret a p.d.f. is that a probability can be
computed as an area under the curve. For example
the probability of the electron being closer than r
0
is
computed as:
{ } dr r h r r
r
}
= <
0
0
0
) ( Pr
r=0 r
h(r)
r
0
r
1
Likewise, the probability of the electron being between r
0
and
r
1
is computed as:
{ } dr r h r r r
r
r
}
= < <
1
0
) ( Pr
1 0
By definition, the p.d.f. does not directly report the probability
of finding an electron at a given fixed distance, r
0
:
{ } ) ( Pr
0
r h r r = =
In fact, the probability for any given distance, r
0
, is 0.
See that:
{ } 0 ) ( Pr
0
0
0
= = =
}
dr r h r r
r
r
A probability is always between 0 and 1 so if we
assume the electron is always found at some distance
from the nucleus then:
More formally, we define the the p.d.f. as a limit:
{ }
(
(
(
A
=
(
A
A + < <
=
}
A +
A A
u
dr r h
u
u u r u
u h
u u
u
u u
) (
lim
Pr
lim ) (
0 0
{ } 1 ) ( 0 Pr
0
= = < <
}
dr r h r
General rule: The summation of p.d.f. over all possible values
must be = 1.
We define a conditional probability as probability of an
event A given that an event B has occurred. This is
written as:
{ } { } { } B B A B A Pr Pr & Pr =
{ }
{ }
{ } B
B A
B A
Pr
& Pr
Pr =
This relation may make more intuitive sense when
rearranged as:
2. Conditional Probability
One can also rearrange relationship to this:
{ } { } { } B A B A B Pr / & Pr Pr =
{ } { } { } B B A B A Pr Pr & Pr =
Note: this is only true if A and B are independent
{ } { } { } B A B A Pr Pr & Pr =
{ } 1 . 0 2 SBE & 1 SBE Pr =
Consider that probability that a given student at JHU takes
both SBE 1 and SBE 2 is 0.10 (1 out 10 students take
both), or:
We can compute the probability of a student taking SB1 as:
For more examples, see tutorials on the internet, such as:
http://www.mathgoodies.com/lessons/vol6/conditional.html
Now consider the probability that a student takes SBE 2
given that the student has taken SBE 1 is 0.9 (9 out 10
students SBE 2 after taking SBE 1), or
{ } 9 . 0 1 SBE | 2 SBE Pr =
{ } { } { } 111 . 0 1 SBE | 2 SBE Pr / 2 SBE & 1 SBE Pr 1 SBE Pr = =
Random Rate Theory
Try to decrease your odds of rolling a 1 on a six-
side die by first rolling a 1 and then taking the
next roll for real.
Reasoning: Odds of rolling two 1s on two
consecutive dice is 1:36. This is low so you are
likely to have a roll higher than 1.
Odds of rolling two 1's on two dice is 1:36, but
conditional probability of rolling a 1 second time
after rolling the first 1 is 1:6 (as you might
expect).
{ } { } { } B B A B A Pr Pr & Pr =
Random Rate Theory
{ }= 1 by followed 1 Rolling Pr
Faulting reasoning: Odds of rolling two 1 on two
dice is 1:36, but conditional probability of rolling
a second 1 after rolling the first 1 is 1:6 (as you
might expect).
{ } { } { } B B A B A Pr Pr & Pr =
{ } { }
36
1
6
1
6
1
1 first the Rolling Pr 1 first the Rolling 1 by followed 1 Rolling Pr
= =
A +
=
A
x x to x
range in A
attached XB
has site A
Pr lim ) t , x ( n
x 0
Note that a more intuitive function describes when an A
site is attached and the A site is between x and x + Ax
We can use rule from basic probability
(
(
(
|
|
|
.
|
\
|
A +
|
|
|
.
|
\
|
A
=
A
x x to x
range in A
&
attached XB
has site A
Pr
x
lim ) t , x ( n
x
1
0
{ } { } { } B B A B A Pr Pr & Pr =
(
(
(
A +
A + A
=
A
x x to x
range in A
x x to x
range in A
attached XB
has site A
x
t x n
x
Pr Pr
1
lim ) , (
0
(
(
(
A + A
-
(
(
(
A +
=
A A
x x to x
range in A
x x x to x
range in A
attached XB
has site A
t x n
x x
Pr
1
lim Pr lim ) , (
0 0
Make a substitution for probability inside limit
Substitute limit above with product of limits below
) , (
) , ( ) , (
t x h t x n t x n - =
Probability Density
Function
Conditional
Probability
) , (
) , ( ) , (
t x h t x n t x n - =
is a probability density function describing the
positions of A sites with respect to equilibrium
XB positions
Model assumes is constant over all possible x
values between -l/2 and l/2 as shown below:
l/2
-l/2
1/l
x
h
( )
( ) ( ) | | ( ) ( ) x n x g x n x f
t
x n
=
c
c
1
( )
( ) ( ) t x n x n
dt
t x dn
,
0
,
of instead use
where state steady Consider
=
Unattached A site fraction Attached A site fraction
site A from detachment of rate
- site A to attachment of rate =
c
c
t
n
( ) ( ) | | ( ) ( ) t x n x g t x n x f , , 1 =
Combine above results:
Can find solution for specific
cases if we define f(x) and g(x)
with units of s
-1
( ) ( )
t
x n
x
x n
v
c
c
=
c
c
( )
( ) ( ) | | ( ) ( ) x n x g x n x f
x
x n
v =
c
c
1
( ) ( )
2
; 0 : 0 g x g x f x = = <
( ) ( )
h
x g
x g
h
x f
x f h x
1 1
; : 0 = = s <
( ) ( )
h
x g
x g x f h x
1
; 0 : = = >
g
4
0
x
f
1
5
3
2
1
g
2
g
1
h
g
f
n g
dx
dn
v
2
=
} }
= dx
v
g
n
dn
2
Apply constraint that if then solution is continuous
at x=0 and x=h. One can write:
Now solve for three region assuming V > 0:
Region 1 -
) ( ) (
) 0 ( ) 0 (
+
+
=
=
h n h n
n n
0 = V
( ) ( )
2
; 0 : 0 g x g x f x = = <
( )
0
,
= =
c
c
dt
t x dn
dx
dn
x
n
where state steady in
Integrate to get:
v
x g
e C x n
2
1
) ( =
T.B.D. constant a is ) ( where
C
o
e C
1
=
xn
h
g
n x
h
f
dx
dn
v
1 1
) 1 ( =
( ) ( )
h
x g
x g
h
x f
x f h x
1 1
; : 0 = = s < Region 2 -
0
2
ln C x
v
g
n + =
xn g n x f
dx
dn
vh
1 1
) 1 ( =
xn g f x f ) (
1 1 1
+ =
) )( (
1 1
1
1 1
n
g f
f
g f x
+
+ =
Rearrange to get:
xdx
vh
g f
g f
f
n
dn
1 1
1 1
1
) (
+
=
+
+
Integrate to get:
2
2
1 1
1 1
1
2
) ln( C
x
vh
g f
g f
f
n +
+
=
+
+
)
`
+
+
=
+
+
2
2
1 1
1 1
1
2
exp C
x
vh
g f
g f
f
n
2
exp
2
1 1
3
1 1
1
)
`
+
=
x
vh
g f
C
g f
f
n
2
3
where
C
e C =
( ) ( )
h
x g
x g x f h x
1
; 0 : = = >
Region 3 -
If we assume shortening then no crossbridges can be
attached at x>h. This is equivalent to n(x,t)=0 for x>h.
Now determine the constants using the continuity
conditions:
) ( ) (
+
= h n h n
2
exp 0
2
1 1
3
1 1
1
)
`
+
=
x
vh
g f
C
g f
f
)
2
2
1 1
1 1
1
3
h
vh
g f
exp(
g f
f
C
+
+
=
Substitute constant back into original equation:
) 0 ( ) 0 (
+
= n n
h x e
g f
f
x n
x h
vh
g f
< <
(
+
=
+
0 for 1 ) (
) - (
2
1 1
1
2 2 1 1
Find C
1
using the other continuity condition:
1
0
1
2
0 C e C n
v
g
= =
-
) ( (
+
=
+
+
2 1 1
2
1 1
1
1 ) 0 (
h
vh
g f
e
g f
f
n
(
+
=
+
2 1 1
2
1 1
1
1
1
h
vh
g f
e
g f
f
C
Substitute constant back into original equation:
Define
where S is a full sarcomere length (~ 2 m), S/2 is a half
sarcomere length, and V is normalized velocity in half
sarcomere lengths per second.
0 1 ) (
2 2 1 1
2
1 1
1
<
(
+
=
+
x e e
g f
f
x n
v
x g
h
vh
g f
for
Make a change of variables:
V
S
v
2
=
) (
1 1
g f
S
h
+ = |
and
The three regions can now be defined as:
Must define rates for XB cycling. Can use the ratios
below:
( ) 0 = > x n h x :
SV
x g
V
e e
g f
f
x n x
2
1 ) ( : 0
1 1
1
(
+
= <
|
)
(
(
+
= < <
V
h
x
e
g f
f
x n h x
|
1 (
1 1
1
2
2
1 ) ( : 0
The following plots on following slides are the result.
16
3
1 1
1
=
+ g f
g
919 . 3
1 1
2
=
+ g f
g
Results for Huxley '57 model
In isometric conditions (V=0), for given distances between X=0
and X=h, there is a high probability of attachment of the A sites to
the myosin. Attached XBs with positive distortion are "pullers".
X
< 0 X
= h
-
X
= h/2
(a)
(c)
(b)
(a)
(b)
(c)
n(h/2) = 0.8
n(h
-
) = 0.8
Results for Huxley '57 model
.
X
< 0 X
= -h/2
X
= h/2
(a)
(c)
(b)
(a)
(b)
(c)
As velocity increases (V>0), probability of attachment of the A site
to the myosin can be above zero for X<0 because XBs may attach
between X=0 and X=h and be dragged to negative distortions.
n(h/2) ~ 0.4 n(-h/2) ~ 0
Results for Huxley '57 model
.
X
< 0 X
= -h/2
X
= h/2
(a)
(c)
(b)
(a)
(b)
(c)
As velocity increases (V>0), the average distortion of the
attached XBs decreases (less positive or more negative). At
V
max
the "pullers" (X>0, i.e. (a)) and "dragger" (X<0, i.e. (b))
cancel so that net tension T = 0. Detached XBs don't contribute.
n(-h/2) ~ 0.1
n(h/2) ~ 0.15
Now we want to generate a Force-Velocity relation.
Velocity is an input parameter, and force is computed.
Must define force per single XB as
Where x is the distortion (= distance from A site to
equilibrium position of attached crossbridge)
Now we want to compute total tension as a the sum of the
the contributions of all the XBs. To do this, we need to
compute an expected value that is analogous to
average value. First define an expected value as:
expected value of u
value of u
probability density
function of finding u
kx force
XB
=
}
>= < du u u u ) pdf(
In our case, we want expected value of tension for all A
sites, both attached and detached. We can write
expected value as:
Force of attached A site
Attached A sites
True p.d.f. of all A site being at distance = x
| | dx x n x h x n kx T
XB
}
)
`
- + >= < ) (
) (
0 ) (
Detached A sites
| | dx x n x h x n
}
)
`
+ = ) (
) (
) (
1
Force of detached A site
) (
) ( ) (
x h x n x n - =
A p.d.f. describing likelihood
of A sites being distance x
from the nearest equilibrium
XB position
Model assumes is constant over all possible x
values between -l/2 and l/2 as shown below:
l/2
-l/2
1/l
x
h
A condition probability of an A
site having an attached XB given
its distance is x from the nearest
equilibrium XB position
h
< <
=
Multiplying the terms produces:
dx x n kx T
XB
}
>= < ) (
dx x n
l
kx
l
l
}
=
2 /
2 /
) (
Substitute for n(x) and integrate to get:
(
(
|
|
.
|
\
|
+
+
+
>= <
| |
|
V
g
g f
e
V
l
kh
g f
f
T
V
XB
2
2
1 1
2
1 1
1
2
1
1 ) 1 ( 1
2
Then substituting into expected value of force:
(
(
|
|
.
|
\
|
+
+ =
> <
> <
=
| |
|
V
g
g f
e
V
T
T
T T
V
XB
XB
2
2
1 1
max
max
2
1
1 ) 1 ( 1 /
For isometric force, set v=0 to get:
l
kh
g f
f
T
XB
2
2
1 1
1
max
+
>= <
Now normalize force by isometric force to get:
) (
1 1
g f
S
h
+ = |
16
3
1 1
1
=
+ g f
g
919 . 3
1 1
2
=
+ g f
g
These parameter give best fit to
experimental data at right
"All models are wrong, but some are useful."
-George Box
Successes of model -
- Good basic framework for cycling XB distribution
- Reproduces Force Velocity relationship
- Reproduces energy use vs. tension relationship
- Superb first attempt given the knowledge of the
system at the time
Problems -
- XB cycle is simplistic
- Restrictive set of conditions
- isotonic, constant velocity
- full activation
- Cycling rate increases with lengthening causing increased
ATP usage in disagreement with experimental results