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Beyond Isometric Twitch:
Utilizing lengthening, shortening and isotonic contraction
tests for muscle function research.
Matt Borkowski
Aurora Scientific
Robert W. Grange, PhD
Virginia Tech
Sponsored by:
InsideScientific is an online educational environment
designed for life science researchers. Our goal is to aid in
the sharing and distribution of scientific information
regarding innovative technologies, protocols, research
tools and laboratory services.
Thank you to our event sponsor
Aurora Scientific, a trusted
provider of instrumentation
for research in muscle
physiology, neuroscience
and material science.
Utilizing lengthening, shortening
and isotonic contraction tests for
muscle function research.
Matt Borkowski
Sales & Support Manager
Aurora Scientific
Copyright 2015 M. Borkowski, Aurora Scientific & InsideScientific. All Rights Reserved.
THE JOURNEY OF A THOUSAND MILES
BEGINS WITH A SINGLE STEP
-- Lao Tzu
• Aurora has served the muscle
community for nearly 20 years.
• Test systems and solutions ranging
from single cells up to the whole
animal.
• Friendly, reliable support.
Cell
Whole
Animal
Fiber
Whole
Muscle
About Aurora Scientific
A NEW CHAPTER BEGINS…
• Aurora Scientific believes in
providing solutions for the
complete characterization of
muscle.
• To completely characterize
the muscle, the 3 types of
contractions must be used.
Complete
Characterization
concentric
isometric
eccentric
What is complete characterization?
What is complete characterization?
• Isometric: Contraction at a
constant muscle length.
• Eccentric: Contraction while
the muscle is lengthening.
• Concentric: Contraction while
the muscle is shortening (can
be isotonic).
Complete
Characterization
concentric
isometric
eccentric
Strengths
 Simple, standardized protocols which
can be used across an array of muscles.
 Excellent way of assessing the absolute
strength of most muscle types.
 Useful for studying the basic
mechanisms behind contraction and
relaxation.
Challenges
Isometric Strengths
 Not the most physiologically relevant
model.
 Limited amount of information can be
obtained from the contractile data.
Strengths
 A good protocol to study muscle injury
and damage and create conditions to
study recovery.
 Excellent for inducing hypertrophy
when applied as an in-vivo training
protocol.
 Models exercise much more accurately
than isometric.
Eccentric Strengths
 A great deal of passive tension is
generated; may necessitate multiple
transducers if studying a broad array of
animal models and muscle types.
 Determining the correct protocol for
specific muscle types and animal
models can be a challenge.
Challenges
Strengths
 Offers a wealth of information within the
contractile data: Power, Work, Force-
Velocity relationship can all be measured.
 Isotonic protocols closely mirror real life
work and exercise.
 Either force or velocity can be controlled,
allowing for multiple ways to test a
particular hypothesis.
Concentric Strengths
 Can be technically challenging to
implement.
 Requires a good deal of configuration
for different muscle types.
Challenges
How Does
it Work ?
• Dual Mode Lever System allows for complete
characterization.
• Single instrument: a motor and force transducer
in one.
• Motor controls and senses position; Force is de-
convolved in electronics from motor current
signal.
• Lever systems range in size to accommodate small
cardiac muscles to limb muscles from larger
mammals.
• Single attachment point opens up the possibility of
performing different assays.
• Lever systems are often paired with experimental
chambers, apparatus and software.
One attachment point: 3 experiment types
In vitroIn situIn vivo
Click Here to see specific Aurora
Muscle Physiology Apparatus
 The foot is secured in a foot-plate mounted
to the dual mode lever system.
 Percutaneous or subcutaneous electrodes
can elicit muscle contraction.
 Aggregate torque of the plantar or dorsi
flexors of the lower limb can be measured.
 Resistance of the pedal can be adjusted to
create isotonic resistance.
 Foot pedal can rotate in conjunction with
contraction to create eccentric or
concentric conditions.
In vivo –
Ankle Torsion
Courtesy of Yan lab, UVA
Courtesy of Granzier lab, Arizona
• The hind limb is stabilized and the muscle of
interest revealed by surgically removing skin.
• The muscle of choice is partially dissected and
the one exposed tendon is tied to the dual
mode lever system.
• Direct muscle or nerve stimulation will produce
a muscle contraction which can be synchronized
with the lever system.
• Technique opens up the possibility to fully
characterize muscles without two easily
accessible tendons.
In situ –
One Free Tendon
• Muscle dissected from animal and
sutured at both free tendons.
• Muscle activated via field stimulation.
• Classical, vertical bath configuration
means only one tendon can attach to
an instrument.
• Only the dual mode lever system
permits tension & length to be
recorded and controlled in this
orientation.
In vitro –
Isolated Muscle
Courtesy of Barton Lab, UFL
Who can benefit from going
beyond isometric?
 Muscle Physiologists
 Exercise Scientists
 Bioengineers & Biologists
 Metabolic & Cardiovascular
Scientists
 Geneticists
 Neuroscientists
 Pharmacologists & Biochemists
 Anyone studying muscle
mechanics
Isometric and Dynamic Muscle
Function Assessment
Robert W. Grange, PhD
Department of Human
Nutrition, Foods and Exercise,
Virginia Tech
Copyright 2015 R.W Grange, Aurora Scientific & InsideScientific. All Rights Reserved.
When muscle is changed by…
Training
Disease
Drug
Genetic manipulation
Other…
Does function change in a meaningful way?
Skeletal Muscle Function in vitro
Patient Prep
‘Hang’ EDL muscle
Operating Room
‘Dissect’ EDL Muscle
Servomotor and
Isometric Force
Transducers
Dual-mode Servomotor For
Dynamic Contractions
Isometric ForceTransducer
Stepper Motor For Maintaining L0
Muscle Clamps
- +
EDL
Isometric and Dynamic
Contractions
Basic muscle in vitro preparation
1. Muscle is mounted in a bath
• Clamped at bottom
• Secured to motor arm at top
2. Electrodes activate muscle
3. Servo Arm
• Stays horizontal (isometric contraction)
• Moves up (eccentric contraction)
• Moves down (concentric contraction)
• Eccentric and concentric are dynamic
contractions
Torque = Force x Moment arm
Ma
Force
Skeletal Muscle
Function in vivo
Mouse Hindlimb
Torque = Force x Moment arm
Ma
Force
Skeletal Muscle
Function in vivo
Dog Hindlimb
Skeletal Muscle
Fundamentals
Epstein M, Herzog W.. Philos Trans R Soc Lond B Biol Sci 2003;358:1445-1452.
Anatomy
• Muscle
• Fascicles
• Fibers
• Myofibrils
• Sarcomere (functional unit of muscle)
• Z lines
• Myosin and Actin: contraction
Muscles: fibers classified by contractile and biochemical properties. Typically Use: Extensor digitorum longus (EDL) – fast ; Soleus – slow
Skeletal Muscle Fiber and Muscle Types
Properties
Fiber Type Classification
Slow-Oxidative (SO) Fast-Oxidative-Glycolytic (FOG) Fast-Glycolytic (FG)
Predominant MHC Type I Type IIA Type IIX or IIB
Contractile Velocity Slow Intermediate High
Glycolytic Potential Low Intermediate High
Oxidative Potential High Intermediate Low
Mitochondrial Density High Intermediate Low
Myoglobin Content High Intermediate Low
Resistance to Fatigue High Intermediate Low
DHPRRyR
Excitation – Contraction
Coupling
• Excitation: Action potential…
• Via T-tubule…
• Releases calcium from RYR of
Sarcoplasmic Reticulum…
• Calcium binds Troponin…
• Myosin and Actin interact:
• Contraction
-
dF/d
t
(Rest
force) Lo
(Peak
force)
Active
force
Time to Peak Force
(TPF)
Half- Relaxation
Time (HRT)
Isometric Twitch
A twitch is the
contractile
response to a single
Action Potential or
single (1 Hz)
electrical
stimulation
Force Summation
t peakF base
Peak Force
(Rest Force)
Isometric Maximal Tetanus
A maximum tetanus
is the result of
maximal summation:
no further increase in
force output despite
increased frequency
of activation.
1 30 50 80 100 150
Frequency (Hz)
0
5
10
15
20
25
30
35
Stress(g/mm
2
)
- Control
- MDX
- MDX:U
-/-
*
*
*
*
*
*
†
†
Stress = force (g)/muscle cross sectional area (mm2); mN/mm2
EDL Muscles
Force Summation
Stress-Frequency
• Stress = force/muscle
cross sectional area
• Stress increases with
increased activation
frequency (i.e.,
summation)
• The maximum stress is
the maximum tetanus
0.00 0.20 0.40 0.60 0.80 1.00
Fractional Load (F/Fat)
0.0
2.0
4.0
6.0
8.0
10.0
ShorteningVelocity(Lf/s)
* *
*
** * * * * * * *
25%
50%
75%
Fractional Load
Tetanic Afterload Method
F at = maximum tetanic Force
Vmax
EDL
Soleus
Force-Velocity
EDL
Soleus
Power –
FxV; Work/Time
• Peak power typically
occurs at a fractional
load of 0.40 (40%) of
maximum load
EDL vs Soleus Muscle Fatigues More Quickly
Examples of Muscle Function
Assessment
1. IGF-1 Injection Into Extraocular Muscle
2. Sox6 Knock Out Mouse
3. Duchenne Muscular Dystrophy (Stretch Injury Protocol)
4. Mechanical Properties – Achilles Tendon stiffness
5. P1 mouse hindlimb in vitro
6. Mouse/dog hindlimb in vivo
Increased extraocular muscle strength with direct injection of insulin-like growth factor-I.
Anderson, Christiansen, Grandt, Grange, McLoon. Invest. Opthalmol Vis Sci 47(6):2461-7,
2006.
CONCLUSIONS:
Direct muscular injection of IGF-I
effectively increases EOM force
generation without the potential
biomechanical hazards of surgery
such as permanently altered muscle
length or insertional position on the
globe.
• 25 ug IGF-1
• rabbit superior rectus
muscle
• assess after 1 week
Increased Extraocular
Muscle Strength
Examples of Muscle Function
Assessment
1. IGF-1 Injection Into Extraocular Muscle
2. Sox6 Knock Out Mouse
3. Duchenne Muscular Dystrophy (Stretch Injury Protocol)
4. Mechanical Properties – Achilles Tendon stiffness
5. P1 mouse hindlimb in vitro
6. Mouse/dog hindlimb in vivo
Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6.
Quiat, Voelker, Pei, Grishin, Grange, Bassel-Duby, Olson. PNAS 108(25):10196-201, 2011
Inhibition of Sox6 leads to a fast to slow phenotype shift
Sox6 - a transcriptional repressor of slow fiber phenotype
(Quiat 2011)
1. Increased red color
Fast to Slow Fiber Shift…
2. Decreased fiber cross sectional area
Force-Velocity
relationship:
Sox6 KO EDL has
decreased Vmax
Fatigue protocol:
Sox6 KO EDL and
Soleus fatigue
less
Muscle Function Changes With Sox6 Knockout
Examples of Muscle Function
Assessment
1. IGF-1 Injection Into Extraocular Muscle
2. Sox6 Knock Out Mouse
3. Duchenne Muscular Dystrophy (Stretch Injury Protocol)
4. Mechanical Properties – Achilles Tendon stiffness
5. P1 mouse hindlimb in vitro
6. Mouse/dog hindlimb in vivo
SarcolemmaDGC
Ervasti, J.M., J.Biol.Chem.,2003. 278(16): p. 13591-13594.
Fiber DGC Absent From
Sarcolemma:
Dystrophic muscle
membrane more
“leaky”
Duchenne Muscular Dystrophy
- +
EDL
Procion Orange
(Mr 631)
Stretch – Injury Protocol
Fiber
0.00 0.25 0.50 0.75 1.00 1.25 1.50
Time (s)
0.0
1.5
3.0
4.5
6.0
7.5
Force(g)
isometric
0.1 Lo stretch
Rate:0.5Lo/s
500 ms 200 ms
Stretch Protocol
• Muscle contracts
isometrically for 500ms
• Then is stretched for 200
ms while contracting
• Stimulation ends at the
peak of the stretch
• The muscle relaxes.
Fast-twitch skeletal muscles of dystrophic mouse
pups are resistant to injury from acute mechanical
stress. Grange, Gainer, Marschner, Talmadge, and Stull.
Am J Physiol Cell Physiol 283(4):C1090-101, 2002.
No
stretch
Five
stretches
Uptake of dye by EDL during stretch injury protocol
in mdx mice aged 4 months ~23%
Fast-twitch skeletal muscles of dystrophic mouse
pups are resistant to injury from acute mechanical
stress. Grange, Gainer, Marschner, Talmadge, and Stull.
Am J Physiol Cell Physiol 283(4):C1090-101, 2002.
- +
EDL
Stretch Injury Protocol:
test microdystrophin gene
therapy in mdx mice
Adeno-associated virus-
mediated microdystrophin
expression protects young
mdx muscle from
contraction-induced
injury.
Liu, Yue, Harper, Grange,
Chamberlain and Duan.
Mol. Ther. 1(2):245-56 2005.
microdystrophin revertant dystrophin
treated
untreated
Examples of Muscle Function
Assessment
1. IGF-1 Injection Into Extraocular Muscle
2. Sox6 Knock Out Mouse
3. Duchenne Muscular Dystrophy (Stretch Injury Protocol)
4. Mechanical Properties – Achilles Tendon stiffness
5. P1 mouse hindlimb in vitro
6. Mouse/dog hindlimb in vivo
Stiffness – change in
force during a change in
muscle length
• for stress-strain
assessment of achilles
tendon to determine
stiffness in mouse pup
aged 15 days
• Grange Lab 2-12-2013
Hindlimb Prep
Examples of Muscle Function
Assessment
1. IGF-1 Injection Into Extraocular Muscle
2. Sox6 Knock Out Mouse
3. Duchenne Muscular Dystrophy (Stretch Injury Protocol)
4. Mechanical Properties – Achilles Tendon stiffness
5. P1 mouse hindlimb in vitro
6. Mouse/dog hindlimb in vivo
- +
EDL
P1 Hindlimb
Force Assessment in
Mouse Pup Hindlimbs
KLHL40 deficiency
destabilizes thin
filament proteins and
promotes nemaline
myopathy
Ankit Garg,1 Jason O’Rourke,1 Chengzu
Long,1 Jonathan Doering,2 Gianina
Ravenscroft,3 Svetlana
Bezprozvannaya,1 Benjamin R.
Nelson,1 Nadine Beetz,1 Lin Li,4 She
Chen,4 Nigel G. Laing,3 Robert W.
Grange,2 Rhonda Bassel-Duby,1 and
Eric N. Olson1 J Clin Invest.
2014;124(8):3529–3539.
A. P8 diaphragm stained with desmin (red); DAPI
(blue) and wheat germ agglutinin (green)
B. EM of longitudinal sections of P8 diaphragm
KLHL40 KOs Have
Disrupted Sarcomeres
Tetanic force
response of P1
hindlimb
Is function disrupted at ages
earlier than P8?
10 mm
EDL
Examples of Muscle Function
Assessment
1. IGF-1 Injection Into Extraocular Muscle
2. Sox6 Knock Out Mouse
3. Duchenne Muscular Dystrophy (Stretch Injury Protocol)
4. Mechanical Properties – Achilles Tendon stiffness
5. P1 mouse hindlimb in vitro
6. Mouse/dog hindlimb in vivo
Mouse Plantar Flexor
Torque in vivo
Torque = Force x Moment arm
Ma
Force
Age- 9 weeks Age- 17 weeks
The Advantage
of In Vivo:
Assess muscle
function over
time between
conditions
Age- 21 weeks Age- 25 weeks
Dog Plantar Flexor
Torque in vivo
Torque = Force x Moment arm
Ma
Force
Eccentric contractions
induce rapid isometric
torque drop in
dystrophin-deficient
dogs.
Tegeler, Grange, Bogan,
Markert, Case, Kornegay,
Childers. Muscle Nerve
42(1):130-2, 2010.
Dog In Vivo #1: Dystrophic Dog Hindlimb Muscle Function
Gene Therapy Prolongs Survival and Restores Function
in Murine and Canine Models of Myotubular Myopathy
Martin K Childers1,2,†, Romain Joubert3, Karine Poulard3, Christelle Moal3,
Robert W Grange4, Jonathan A Doering4, Michael W Lawlor5,6, Branden E.
Rider5, Thibaud Jamet3, Nathalie Danièle3, Samia Martin3, Christel Rivière3,
Thomas Soker6, Caroline Hammer3, Laetitia Van Wittenberghe3, Mandy
Lockard7, Xuan Guan7, Melissa Goddard7, Erin Mitchell7, Jane Barber7, J. Koudy
Williams7, David L Mack1, Mark E Furth8, Alban Vignaud3, Carole Masurier3,
Fulvio Mavilio3, Philippe Moullier3,9,10, Alan H Beggs5,†, and Anna Buj-Bello3,†
Sci Transl Med. 2014 January 22; 6(220): 220ra10. doi:10.1126/scitranslmed.3007523.
Dog In Vivo #2: MTM-Deficient Dog Hindlimb
Muscle Function
“Loss-of-function mutations in the myotubularin gene
(MTM1) cause X-linked myotubular myopathy (XLMTM),
a fatal, congenital pediatric disease that affects the entire
skeletal musculature.” Childers et al., 2014
Dr. Childers (University of Washington) has a colony of XLMTM dogs.
MTM1 encodes a lipid phosphatase; primarily effects skeletal muscle:
• Hypotrophic fibers
• Muscle structural abnormalities
• Generalized weakness
There is no known cure… what are the functional outcomes of gene therapy?
Childers et al., Sci Transl Med. 6(220), 2014
Hindlimb infusion of XLMTM
dogs with AAV8-MTM1 (canine)
AAV-infused Non-infused
VL
CT
Baseline age: 9 wks
6 wks post-
inf
8 wks post-
inf
14 wks
post-inf
1 year
post-inf
Acknowledgements
The authors and co-authors listed herein: thank you for
providing me the opportunity to contribute to your great work!
Audentes
Therapeutics
?
Muscle function:
Physiological
Interpretation is
Essential (PIE)
PIE
Robert W. Grange, PhD
Virginia Tech
rgrange@vt.edu
Matt Borkowski
Aurora Scientific
mattb@aurorascientific.com
Thank You!
For additional information on Aurora
Scientific instruments specially designed
for muscle function research please visit:
http://www.aurorascientific.com/

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Beyond Isometric Twitch: Utilizing lengthening, shortening and isotonic contraction tests for muscle function research

  • 1. Beyond Isometric Twitch: Utilizing lengthening, shortening and isotonic contraction tests for muscle function research. Matt Borkowski Aurora Scientific Robert W. Grange, PhD Virginia Tech Sponsored by:
  • 2. InsideScientific is an online educational environment designed for life science researchers. Our goal is to aid in the sharing and distribution of scientific information regarding innovative technologies, protocols, research tools and laboratory services.
  • 3. Thank you to our event sponsor Aurora Scientific, a trusted provider of instrumentation for research in muscle physiology, neuroscience and material science.
  • 4. Utilizing lengthening, shortening and isotonic contraction tests for muscle function research. Matt Borkowski Sales & Support Manager Aurora Scientific Copyright 2015 M. Borkowski, Aurora Scientific & InsideScientific. All Rights Reserved.
  • 5. THE JOURNEY OF A THOUSAND MILES BEGINS WITH A SINGLE STEP -- Lao Tzu
  • 6. • Aurora has served the muscle community for nearly 20 years. • Test systems and solutions ranging from single cells up to the whole animal. • Friendly, reliable support. Cell Whole Animal Fiber Whole Muscle About Aurora Scientific
  • 7. A NEW CHAPTER BEGINS…
  • 8.
  • 9. • Aurora Scientific believes in providing solutions for the complete characterization of muscle. • To completely characterize the muscle, the 3 types of contractions must be used. Complete Characterization concentric isometric eccentric What is complete characterization?
  • 10. What is complete characterization? • Isometric: Contraction at a constant muscle length. • Eccentric: Contraction while the muscle is lengthening. • Concentric: Contraction while the muscle is shortening (can be isotonic). Complete Characterization concentric isometric eccentric
  • 11. Strengths  Simple, standardized protocols which can be used across an array of muscles.  Excellent way of assessing the absolute strength of most muscle types.  Useful for studying the basic mechanisms behind contraction and relaxation. Challenges Isometric Strengths  Not the most physiologically relevant model.  Limited amount of information can be obtained from the contractile data.
  • 12. Strengths  A good protocol to study muscle injury and damage and create conditions to study recovery.  Excellent for inducing hypertrophy when applied as an in-vivo training protocol.  Models exercise much more accurately than isometric. Eccentric Strengths  A great deal of passive tension is generated; may necessitate multiple transducers if studying a broad array of animal models and muscle types.  Determining the correct protocol for specific muscle types and animal models can be a challenge. Challenges
  • 13. Strengths  Offers a wealth of information within the contractile data: Power, Work, Force- Velocity relationship can all be measured.  Isotonic protocols closely mirror real life work and exercise.  Either force or velocity can be controlled, allowing for multiple ways to test a particular hypothesis. Concentric Strengths  Can be technically challenging to implement.  Requires a good deal of configuration for different muscle types. Challenges
  • 15. • Dual Mode Lever System allows for complete characterization. • Single instrument: a motor and force transducer in one. • Motor controls and senses position; Force is de- convolved in electronics from motor current signal.
  • 16. • Lever systems range in size to accommodate small cardiac muscles to limb muscles from larger mammals. • Single attachment point opens up the possibility of performing different assays. • Lever systems are often paired with experimental chambers, apparatus and software.
  • 17. One attachment point: 3 experiment types In vitroIn situIn vivo Click Here to see specific Aurora Muscle Physiology Apparatus
  • 18.  The foot is secured in a foot-plate mounted to the dual mode lever system.  Percutaneous or subcutaneous electrodes can elicit muscle contraction.  Aggregate torque of the plantar or dorsi flexors of the lower limb can be measured.  Resistance of the pedal can be adjusted to create isotonic resistance.  Foot pedal can rotate in conjunction with contraction to create eccentric or concentric conditions. In vivo – Ankle Torsion Courtesy of Yan lab, UVA
  • 19. Courtesy of Granzier lab, Arizona • The hind limb is stabilized and the muscle of interest revealed by surgically removing skin. • The muscle of choice is partially dissected and the one exposed tendon is tied to the dual mode lever system. • Direct muscle or nerve stimulation will produce a muscle contraction which can be synchronized with the lever system. • Technique opens up the possibility to fully characterize muscles without two easily accessible tendons. In situ – One Free Tendon
  • 20. • Muscle dissected from animal and sutured at both free tendons. • Muscle activated via field stimulation. • Classical, vertical bath configuration means only one tendon can attach to an instrument. • Only the dual mode lever system permits tension & length to be recorded and controlled in this orientation. In vitro – Isolated Muscle Courtesy of Barton Lab, UFL
  • 21. Who can benefit from going beyond isometric?  Muscle Physiologists  Exercise Scientists  Bioengineers & Biologists  Metabolic & Cardiovascular Scientists  Geneticists  Neuroscientists  Pharmacologists & Biochemists  Anyone studying muscle mechanics
  • 22. Isometric and Dynamic Muscle Function Assessment Robert W. Grange, PhD Department of Human Nutrition, Foods and Exercise, Virginia Tech Copyright 2015 R.W Grange, Aurora Scientific & InsideScientific. All Rights Reserved.
  • 23. When muscle is changed by… Training Disease Drug Genetic manipulation Other… Does function change in a meaningful way?
  • 25. Patient Prep ‘Hang’ EDL muscle Operating Room ‘Dissect’ EDL Muscle
  • 26. Servomotor and Isometric Force Transducers Dual-mode Servomotor For Dynamic Contractions Isometric ForceTransducer Stepper Motor For Maintaining L0 Muscle Clamps
  • 27. - + EDL Isometric and Dynamic Contractions Basic muscle in vitro preparation 1. Muscle is mounted in a bath • Clamped at bottom • Secured to motor arm at top 2. Electrodes activate muscle 3. Servo Arm • Stays horizontal (isometric contraction) • Moves up (eccentric contraction) • Moves down (concentric contraction) • Eccentric and concentric are dynamic contractions
  • 28. Torque = Force x Moment arm Ma Force Skeletal Muscle Function in vivo Mouse Hindlimb
  • 29. Torque = Force x Moment arm Ma Force Skeletal Muscle Function in vivo Dog Hindlimb
  • 31. Epstein M, Herzog W.. Philos Trans R Soc Lond B Biol Sci 2003;358:1445-1452. Anatomy • Muscle • Fascicles • Fibers • Myofibrils • Sarcomere (functional unit of muscle) • Z lines • Myosin and Actin: contraction
  • 32. Muscles: fibers classified by contractile and biochemical properties. Typically Use: Extensor digitorum longus (EDL) – fast ; Soleus – slow Skeletal Muscle Fiber and Muscle Types Properties Fiber Type Classification Slow-Oxidative (SO) Fast-Oxidative-Glycolytic (FOG) Fast-Glycolytic (FG) Predominant MHC Type I Type IIA Type IIX or IIB Contractile Velocity Slow Intermediate High Glycolytic Potential Low Intermediate High Oxidative Potential High Intermediate Low Mitochondrial Density High Intermediate Low Myoglobin Content High Intermediate Low Resistance to Fatigue High Intermediate Low
  • 33. DHPRRyR Excitation – Contraction Coupling • Excitation: Action potential… • Via T-tubule… • Releases calcium from RYR of Sarcoplasmic Reticulum… • Calcium binds Troponin… • Myosin and Actin interact: • Contraction
  • 34. - dF/d t (Rest force) Lo (Peak force) Active force Time to Peak Force (TPF) Half- Relaxation Time (HRT) Isometric Twitch A twitch is the contractile response to a single Action Potential or single (1 Hz) electrical stimulation
  • 36. t peakF base Peak Force (Rest Force) Isometric Maximal Tetanus A maximum tetanus is the result of maximal summation: no further increase in force output despite increased frequency of activation.
  • 37. 1 30 50 80 100 150 Frequency (Hz) 0 5 10 15 20 25 30 35 Stress(g/mm 2 ) - Control - MDX - MDX:U -/- * * * * * * † † Stress = force (g)/muscle cross sectional area (mm2); mN/mm2 EDL Muscles Force Summation Stress-Frequency • Stress = force/muscle cross sectional area • Stress increases with increased activation frequency (i.e., summation) • The maximum stress is the maximum tetanus
  • 38. 0.00 0.20 0.40 0.60 0.80 1.00 Fractional Load (F/Fat) 0.0 2.0 4.0 6.0 8.0 10.0 ShorteningVelocity(Lf/s) * * * ** * * * * * * * 25% 50% 75% Fractional Load Tetanic Afterload Method F at = maximum tetanic Force Vmax EDL Soleus Force-Velocity
  • 39. EDL Soleus Power – FxV; Work/Time • Peak power typically occurs at a fractional load of 0.40 (40%) of maximum load
  • 40. EDL vs Soleus Muscle Fatigues More Quickly
  • 41. Examples of Muscle Function Assessment 1. IGF-1 Injection Into Extraocular Muscle 2. Sox6 Knock Out Mouse 3. Duchenne Muscular Dystrophy (Stretch Injury Protocol) 4. Mechanical Properties – Achilles Tendon stiffness 5. P1 mouse hindlimb in vitro 6. Mouse/dog hindlimb in vivo
  • 42. Increased extraocular muscle strength with direct injection of insulin-like growth factor-I. Anderson, Christiansen, Grandt, Grange, McLoon. Invest. Opthalmol Vis Sci 47(6):2461-7, 2006. CONCLUSIONS: Direct muscular injection of IGF-I effectively increases EOM force generation without the potential biomechanical hazards of surgery such as permanently altered muscle length or insertional position on the globe. • 25 ug IGF-1 • rabbit superior rectus muscle • assess after 1 week Increased Extraocular Muscle Strength
  • 43. Examples of Muscle Function Assessment 1. IGF-1 Injection Into Extraocular Muscle 2. Sox6 Knock Out Mouse 3. Duchenne Muscular Dystrophy (Stretch Injury Protocol) 4. Mechanical Properties – Achilles Tendon stiffness 5. P1 mouse hindlimb in vitro 6. Mouse/dog hindlimb in vivo
  • 44. Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6. Quiat, Voelker, Pei, Grishin, Grange, Bassel-Duby, Olson. PNAS 108(25):10196-201, 2011 Inhibition of Sox6 leads to a fast to slow phenotype shift Sox6 - a transcriptional repressor of slow fiber phenotype
  • 45. (Quiat 2011) 1. Increased red color Fast to Slow Fiber Shift… 2. Decreased fiber cross sectional area
  • 46. Force-Velocity relationship: Sox6 KO EDL has decreased Vmax Fatigue protocol: Sox6 KO EDL and Soleus fatigue less Muscle Function Changes With Sox6 Knockout
  • 47. Examples of Muscle Function Assessment 1. IGF-1 Injection Into Extraocular Muscle 2. Sox6 Knock Out Mouse 3. Duchenne Muscular Dystrophy (Stretch Injury Protocol) 4. Mechanical Properties – Achilles Tendon stiffness 5. P1 mouse hindlimb in vitro 6. Mouse/dog hindlimb in vivo
  • 48. SarcolemmaDGC Ervasti, J.M., J.Biol.Chem.,2003. 278(16): p. 13591-13594. Fiber DGC Absent From Sarcolemma: Dystrophic muscle membrane more “leaky” Duchenne Muscular Dystrophy
  • 49. - + EDL Procion Orange (Mr 631) Stretch – Injury Protocol Fiber
  • 50. 0.00 0.25 0.50 0.75 1.00 1.25 1.50 Time (s) 0.0 1.5 3.0 4.5 6.0 7.5 Force(g) isometric 0.1 Lo stretch Rate:0.5Lo/s 500 ms 200 ms Stretch Protocol • Muscle contracts isometrically for 500ms • Then is stretched for 200 ms while contracting • Stimulation ends at the peak of the stretch • The muscle relaxes.
  • 51. Fast-twitch skeletal muscles of dystrophic mouse pups are resistant to injury from acute mechanical stress. Grange, Gainer, Marschner, Talmadge, and Stull. Am J Physiol Cell Physiol 283(4):C1090-101, 2002. No stretch Five stretches
  • 52. Uptake of dye by EDL during stretch injury protocol in mdx mice aged 4 months ~23% Fast-twitch skeletal muscles of dystrophic mouse pups are resistant to injury from acute mechanical stress. Grange, Gainer, Marschner, Talmadge, and Stull. Am J Physiol Cell Physiol 283(4):C1090-101, 2002.
  • 53. - + EDL Stretch Injury Protocol: test microdystrophin gene therapy in mdx mice
  • 54. Adeno-associated virus- mediated microdystrophin expression protects young mdx muscle from contraction-induced injury. Liu, Yue, Harper, Grange, Chamberlain and Duan. Mol. Ther. 1(2):245-56 2005. microdystrophin revertant dystrophin treated untreated
  • 55. Examples of Muscle Function Assessment 1. IGF-1 Injection Into Extraocular Muscle 2. Sox6 Knock Out Mouse 3. Duchenne Muscular Dystrophy (Stretch Injury Protocol) 4. Mechanical Properties – Achilles Tendon stiffness 5. P1 mouse hindlimb in vitro 6. Mouse/dog hindlimb in vivo
  • 56. Stiffness – change in force during a change in muscle length • for stress-strain assessment of achilles tendon to determine stiffness in mouse pup aged 15 days • Grange Lab 2-12-2013 Hindlimb Prep
  • 57. Examples of Muscle Function Assessment 1. IGF-1 Injection Into Extraocular Muscle 2. Sox6 Knock Out Mouse 3. Duchenne Muscular Dystrophy (Stretch Injury Protocol) 4. Mechanical Properties – Achilles Tendon stiffness 5. P1 mouse hindlimb in vitro 6. Mouse/dog hindlimb in vivo
  • 58. - + EDL P1 Hindlimb Force Assessment in Mouse Pup Hindlimbs
  • 59. KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy Ankit Garg,1 Jason O’Rourke,1 Chengzu Long,1 Jonathan Doering,2 Gianina Ravenscroft,3 Svetlana Bezprozvannaya,1 Benjamin R. Nelson,1 Nadine Beetz,1 Lin Li,4 She Chen,4 Nigel G. Laing,3 Robert W. Grange,2 Rhonda Bassel-Duby,1 and Eric N. Olson1 J Clin Invest. 2014;124(8):3529–3539.
  • 60. A. P8 diaphragm stained with desmin (red); DAPI (blue) and wheat germ agglutinin (green) B. EM of longitudinal sections of P8 diaphragm KLHL40 KOs Have Disrupted Sarcomeres Tetanic force response of P1 hindlimb Is function disrupted at ages earlier than P8? 10 mm EDL
  • 61. Examples of Muscle Function Assessment 1. IGF-1 Injection Into Extraocular Muscle 2. Sox6 Knock Out Mouse 3. Duchenne Muscular Dystrophy (Stretch Injury Protocol) 4. Mechanical Properties – Achilles Tendon stiffness 5. P1 mouse hindlimb in vitro 6. Mouse/dog hindlimb in vivo
  • 62. Mouse Plantar Flexor Torque in vivo Torque = Force x Moment arm Ma Force
  • 63. Age- 9 weeks Age- 17 weeks The Advantage of In Vivo: Assess muscle function over time between conditions Age- 21 weeks Age- 25 weeks
  • 64. Dog Plantar Flexor Torque in vivo Torque = Force x Moment arm Ma Force
  • 65. Eccentric contractions induce rapid isometric torque drop in dystrophin-deficient dogs. Tegeler, Grange, Bogan, Markert, Case, Kornegay, Childers. Muscle Nerve 42(1):130-2, 2010. Dog In Vivo #1: Dystrophic Dog Hindlimb Muscle Function
  • 66. Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy Martin K Childers1,2,†, Romain Joubert3, Karine Poulard3, Christelle Moal3, Robert W Grange4, Jonathan A Doering4, Michael W Lawlor5,6, Branden E. Rider5, Thibaud Jamet3, Nathalie Danièle3, Samia Martin3, Christel Rivière3, Thomas Soker6, Caroline Hammer3, Laetitia Van Wittenberghe3, Mandy Lockard7, Xuan Guan7, Melissa Goddard7, Erin Mitchell7, Jane Barber7, J. Koudy Williams7, David L Mack1, Mark E Furth8, Alban Vignaud3, Carole Masurier3, Fulvio Mavilio3, Philippe Moullier3,9,10, Alan H Beggs5,†, and Anna Buj-Bello3,† Sci Transl Med. 2014 January 22; 6(220): 220ra10. doi:10.1126/scitranslmed.3007523. Dog In Vivo #2: MTM-Deficient Dog Hindlimb Muscle Function
  • 67. “Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature.” Childers et al., 2014 Dr. Childers (University of Washington) has a colony of XLMTM dogs. MTM1 encodes a lipid phosphatase; primarily effects skeletal muscle: • Hypotrophic fibers • Muscle structural abnormalities • Generalized weakness There is no known cure… what are the functional outcomes of gene therapy?
  • 68. Childers et al., Sci Transl Med. 6(220), 2014 Hindlimb infusion of XLMTM dogs with AAV8-MTM1 (canine) AAV-infused Non-infused VL CT Baseline age: 9 wks 6 wks post- inf 8 wks post- inf 14 wks post-inf 1 year post-inf
  • 69. Acknowledgements The authors and co-authors listed herein: thank you for providing me the opportunity to contribute to your great work! Audentes Therapeutics
  • 71. Robert W. Grange, PhD Virginia Tech rgrange@vt.edu Matt Borkowski Aurora Scientific mattb@aurorascientific.com Thank You! For additional information on Aurora Scientific instruments specially designed for muscle function research please visit: http://www.aurorascientific.com/