Kinetics of Muscle Contraction and Relaxation

Bin Liu

Ph.D.

Phone: (614) 292-3925

Email: liu.591@osu.edu

DHLRI 525

Department of Physiology and Cell Biology, The Ohio State University

Environmental

Whole Body

Muscle (Organ)

Muscle (Molecular)

Factors Controlling SPEED of Movement

Muscle (Cellular)

Ultimate Factors Controlling SPEED

Need the Strength to Meet the Demand Motor Units and Recruitment

Amplifying Velocity/Distance - Lever Systems, Muscle Length and Geometry

Levers Detrimental to Force Levers Amplify Distance/Velocity

Energy Supply Also Controls SPEED

Oxidation Sustains Duration BUT NOT Speed

Glycolytic Sources SUPPORT Speed BUT NOT Duration

Striding Requires Contraction and Relaxation

For Sustained SPEEDS the Muscle Groups Must Contract as well as Relax – Otherwise No Continued Movement

SPEED Is Determined by Fiber Types and Fatigue

Different Fiber Types Contract and Relax at Different Rates

Fatigue Can Slow the Rates of Contraction and Relaxation – Again a Fiber Type Phenomenon

Time

[Ca2+]Plasm

a M

embra

ne

Plasma Membrane

T-Tubule

Sarco

plas

mic

Ret

icul

um Sarcoplasmic Reticulum

Cellular Regulation of Muscle Contraction

1) Action Potential 2) Calcium Transient

Calcium

3) Calcium Binds Troponin C

Actin

TropomyosinTroponin Complex

- Ca2+

+ Ca2+ Myosin Binding Site

4) Myosin Power Stroke

Power Stroke

Actin

Myosin

Actin

Myosin

5) Force Production

ATP Driven

–Ca2+ Relaxed

+Ca2+ Contracted

SR Ca2+ ATPase

Calcium Transient

(Shortening or Force Generation)

The Action Potential, Rise in Calcium and Activation of the Thin Filament All Occur Much Faster than Contraction

Rate-Limiting Step for Contraction

Biochemical Rate Limiting Step of Contraction

POWER STROKE Associated with Pi

Release

The Myosin Neck is also a Lever Arm

(Coupling of the Chemical Changes to Mechanical Changes)

ATPase Rate Correlates with Maximal Speed of Muscle Contraction

The Load that Myosin Has to Work Against Alters Velocity

A

B

C

D

Maximal Velocity (VMAX)

Tug-of-War

A

To bear the load more myosins need to be simultaneously bound leading to drag.

Even at the single molecule level velocity slows due to ADP release slowing with load.

B

C

D

Different Fiber Types Contract and RELAX at Different Rates

SlowFastSuper Fast

~200 Hz ~90 Hz

~5 Hz ~2 Hz

- ADP~250 Hz

Time

Amp

Fall in the Ca2+ Transient

1 2

Ca2+ Off TnC

Actin

TropomyosinTroponin Complex

- Ca2+

+ Ca2+ Myosin Binding Site

Time

[Ca2+

]

3Cross Bridge Dissociation

Power Stroke

Actin

Myosin

Actin

Myosin

ATP Driven

Three Biochemical Influences on Striated Muscle Relaxation

SR Ca2+ ATPase

XX

TBQ Inhibition of SR Ca2+-ATPase

Control

Inhibition of the SR Ca2+-ATPase Inhibits Relaxation: Ca2+ Levels Must Decline for Relaxation to Occur

Parvalbumin Increases the Rate of Muscle Relaxation by Giving the SR Ca2+-ATPase a Helping EF-Hand

+Parv - Parv

Mg-Parv Ca-Parv

SR Ca2+ ATPase

Ca2+ Displaces Mg2+ from Parv

SR Removes Ca2+ from Parv

Parvalbumin Acts as a Delayed and Temporary Ca2+ Buffer

Canonical Calcium Binding Loop

The EF-Hand is the Most Common Calcium Binding Motif used to Decode the Calcium Signal

EF-HandCrystal Structure of Cardiac TnC

Helix

Helix

Loop

N-Terminal Regulatory Domain

C-Terminal Structural Domain

> 500 known EF-hand proteins with >300 unique sequencesWhat is the significance? >1000-fold variation in affinity and rate constants

The Regulatory Domain of Troponin C Acts as a Ca2+ Dependent Switch

Ca2+1) Troponin C – Binds Calcium2) Troponin I – Inhibits Cross-Bridge Binding3) Troponin T – Binds Tropomyosin

The Troponin Complex Contains Three Proteins

Apo State

Ca2+ Saturated

Ca2+ Saturated + TnI

Ca2+ TnI

Ca2+ Dissociation Rates from Fluorescent TnC Mutants

Rates of Relaxation with TnC Mutants

Effect of ‘Slower’ or ‘Faster’ Troponin C Mutants on Skeletal Muscle Relaxation

Slower TnC (5/s)

control TnC (11/s)

Faster TnC (16/s)

Slower TnC

Faster TnC

Control TnC

CLASSIFICATION OF SKELETAL MUSCLE FIBERS - All Systems “TUNED” for a Particular Function -

Classification system of muscle fibers is based on:Rate of ATP utilization and capacity to re-synthesize ATPPhysiological implications of these parameters

Muscles are heterogeneous with different proportions of fiber types depending on function

Studies in Biology #11: Muscle. 2nd Edition, D.R. Wilkie 1979.

Human Physiology, 9th edition by E.P. Widmaier, H. Raff and K.T. Strang, 2004

News Physiol Sci. 2001 Apr;16:49-55. Skeletal and cardiac muscle contractile activation: tropomyosin "rocks and rolls".Gordon AM, Regnier M, Homsher E.

Pflugers Arch. 2005 Mar;449(6):505-17. Epub 2004 Nov 30. Sarcomeric determinants of striated muscle relaxation kinetics.

Poggesi C, Tesi C, Stehle R.

Annu Rev Physiol. 2005;67:39-67. Calcium, thin filaments, and the integrative biology of cardiac contractility.

Kobayashi T, Solaro RJ.

Am J Physiol. 1996 Feb;270(2 Pt 1):C411-7. Parvalbumin relaxes frog skeletal muscle when sarcoplasmic reticulum Ca(2+)-ATPase is inhibited. Jiang Y, Johnson JD, Rall JA.

Annu Rev Physiol. 2006;68:193-221; Design and Function of Superfast Muscles: New Insights into the Physiology of Skeletal Muscle. Rome LC.

Assorted References (contact me if you would like more)