Skeletal Muscle Function Changes with Aging and Exercise: From the Myosin Molecule to the Whole Muscle

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Skeletal Muscle Function Changes with Aging and Exercise: From

Skeletal Muscle Function Changes with Aging and Exercise: From

the Myosin Molecule to the Whole Muscle

the Myosin Molecule to the Whole Muscle

Mark S. Miller

University of Massachusetts Amherst

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Skeletal Muscle Function Changes with Aging and Exercise:

From the Myosin Molecule to the Whole Muscle

M.S. Miller

Disclosure

Molecular level

Single fiber level

Whole muscle level

Whole body level

Areas of expertise

Myofibrillar level

Single fiber level

Whole muscle level

Muscle Function

Previous studies

Heart Failure

Aging

Cancer

Heart Failure + Resistance training

Knee Osteoarthritis + Resistance training (Submitted)

Knee Osteoarthritis

Why study myosin-actin interactions in aging skeletal muscle?

•

Whole skeletal muscle power output decreases with age, which leads to

functional limitations and disability

•

Understanding mechanisms behind muscle power loss will aid in developing

pharmacological and/or exercise countermeasures

Power = Force × Velocity

Whole muscle size:

Aging

Single fiber performance:

Force

Velocity

Loss of muscle quality

Are myosin-actin interactions affected by age?

If so, can these altered myosin-actin interactions explain reductions

in whole muscle power output?

Young

Older

Molecular level

Single fiber level

Whole muscle level

Whole body level

Functional performance

(peak O

₂

consumption)

Physical activity

Myosin off

Myosin on

Myosin-actin interactions or cross-bridge kinetics

Myosin attachment time (ton)

Myosin detachment time (toff) Time F o rc e

Vale and Milligan (2000) Science

Time

Myosin off

Myosin on

Myosin attachment time (ton)

Myosin detachment time (toff)

F

_XB 1 2 3 4 5 6 7 8 9 10 M y os in head num be r ( N )

Myosin-actin cross-bridge kinetics

Time F o rc e 2 myosin heads Force:

Time

0.2 × 10 × F_XB = 2 F_XB

Myosin off

Myosin on

Myosin attachment time (ton)

Myosin detachment time (toff)

F

_XB

Isometric force (F

_Iso

):

F

_Iso

=

N F

_XB

t

_on

+ t

_off

t

_on 1 2 3 4 5 6 7 8 9 10 M y os in head num be r ( N ) Force (F_Iso):

Myosin-actin cross-bridge kinetics

MHC I

MHC IIA

MHC IIX

Slow

Fast

Fastest

Shortening

Velocity

Velocity: 1.0 ML/s

Velocity ∝

t

_on

1

D’Antona et al. (2003) J Physiol M axi m um t ensi on (mN /mm 2 ) MHC IIA (Fast) MHC I (Slow) Young Older Immobilized Older Time 0.2 × 10 × F_XB = 2 F_XB

Myosin off

Myosin on

Myosin attachment time (ton)

Myosin detachment time (toff)

F

_XB

Isometric force (F

_Iso

):

F

_Iso

=

N F

_XB

t

_on

+ t

_off

t

_on 1 2 3 4 5 6 7 8 9 10 M y os in head num be r ( N ) Force (F_Iso):

Myosin-actin cross-bridge kinetics

Velocity: 1.0 ML/s

Velocity ∝

t

_on

Time 0.25 × 10 × F_XB = 2.5 F_XB 0.2 × 8 × FXB = 1.6 FXB 0.2 × 10 × F_XB = 2 F_XB

Myosin off

Myosin on

Myosin attachment time (ton)

Myosin detachment time (toff)

F

_XB

Isometric force (F

_Iso

):

F

_Iso

=

N F

_XB

t

_on

+ t

_off

t

_on 1 2 3 4 5 6 7 8 9 10 M y os in head num be r ( N ) N by 20% 1 2 3 4 5 6 7 8 t_on by 25% 1 2 3 4 5 6 7 8 9 10 Force (F_Iso):

Velocity ∝

t

_on

1

1.0 ML/s 1.0 ML/s 0.80 ML/s Aging decreases single fiber force Young

Aging decreases single fiber velocity

Hypothesis:

Myosin-actin cross-bridge kinetics

Myosin-actin cross-bridge kinetics

Myosin off

Myosin on

Myosin attachment time (ton)

Myosin detachment time (toff)

F

_XB Pre-power stroke Post-power stroke Myosin weakly bound Myosin strongly bound For w a rd R ev er s e

Age by Sex = 0.08

Age

Age by Sex

Age

Female

Male

***

***

Asterisks indicate significant difference (*** = P<0.001) between young and older females

MHC I

(Slow)

MHC IIA

(Fast)

= Young

= Older

Rate of force production

Age or Age by Sex =

Molecular level

Single fiber level

Whole muscle level

Whole body level

Functional performance

(peak O

₂

consumption)

Physical activity

Isometric torque

Isokinetic power

Isometric tension

Myosin attachment time

Rate of force production

_{Slower cross-bridge kinetics}

with age

Power = Force x Velocity

Contractile velocity

(Predicted)

Preliminary findings from knee osteoarthritis + training study

P

ow

e

r

(mN

/mm

2

x M

L

/s)

Tension (mN/mm

2

₎

Male, Pre

Female, Pre

MHC I

= Pre-resistance training

= Post-resistance training

Female

Male

Female

Male

M

y

os

in

a

tta

c

hme

nt ti

me

or

t

on

(ms

)

B

(mN

/mm

2

)

M

a

x

imum T

e

ns

ion

(mN

/mm

2

)

P

ow

e

r

(mN

/mm

2

x M

L

/s)

Tension (mN/mm

2

₎

Sex

Train by Sex

Train by Sex

Train by Sex

Male, Post

Male, Pre

Female, Post

Female, Pre

Preliminary findings from knee osteoarthritis + training study

MHC I

M

ol

ec

ul

ar

to

w

hol

e m

us

c

le

func

ti

on

Time

Aging Aging + Disease RT PT

PT = Power Training, RT = Resistance Training

Males

Females

Time

Aging Aging + Disease Aerobic RT PT RT and PT RT Aerobic Aerobic

Future Directions

Previously measured

This is a novel approach in that exercise programs would be developed for

clinical applications by correcting the fundamental molecular and cellular

pathology of aging and disease.

Aerobic RT

Acknowledgments

Joan Braddock

Damien Callahan

Rich Lachapelle

Michael Previs

Bertrand Tanner

Kimberly Ward

Katie Bedard

Nicholas Bedrin*

James Berking*

Hilary Kulakowski

Mariel Maling

Andrew Sweeney*

Juliana Yellin

Volunteers

CRC Staff

Philip Ades

Michael Toth

Brad Palmer

David Maughan

Jim Vigoreaux

Single skinned fiber muscle mechanics (sinusoidal analysis)

Isolate and “skin” single muscle fiber.

Mount fiber with t-clips to force

transducer and servo motor.

Measure elastic modulus, viscous

modulus, and work output by oscillating

the muscle from 0.125 to 200 Hz

(sinusoidal analysis)

Expose fiber to exposed to

different Ca

2+

_conditions

Use sinusoidal analysis and curve

fitting parameters to calculate a

myosin attachment time (t

_on

)

Elastic Modulus (kN/m2)

-4000

-2000

0

2000

4000

V

is

c

ous

M

odul

us

(

k

N

/m

2

)

-2000

-1000

0

1000

2000

3000

0

3000

6000

-2000

-1000

0

1000

2000

3000

4000

C

B

b

c

0.5 Hz

200 Hz

A

k

π / 2













+

+













+

−

=

ω

ω

ω

ω

ω

ω

i

i

i

i

i

Y

c

2

π

C

b

2

π

B

)

A(

)

(

k

Curve fitting parameters for sinusoidal analysis data

Palmer et al. (2007) Biophys J

(2πc)

-1

_{is equivalent to myosin}