Transcript Lecture 25

Muscles are remarkably adaptive. Any doubts?
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Musculoskeletal Issues
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Disease / genetics
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Muscular dystrophy
Cancer / AIDS cachexia
Obesity / diabetes
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Casting
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Bedrest
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Spinal cord or nerve injury
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Surgery / rehab / disuse
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Aging
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Microgravity
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Sarcomere (Basic
Contractile Apparatus)
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Cellular Energy Production
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TYPE of FIBER
Characteristic
Slow Oxidative
(I)
Fast Oxidative
(IIa)
Fast Glycolytic
(IIb)
Myosin ATPase activity
LOW
HIGH
HIGH
Speed of Contraction
SLOW
FAST
FAST
Fatigue Resistance
HIGH
Intermediate
LOW
Oxidative Capacity
HIGH
HIGH
LOW
Anaerobic Enzyme Content
LOW
Intermediate
HIGH
Mitochondria
MANY
MANY
FEW
Capillaries
MANY
MANY
FEW
Myoglobin Content
HIGH
HIGH
LOW
Color of Fiber
RED
RED
WHITE
Glycogen Content
LOW
Intermediate
HIGH
Myoglobin Content
HIGH
HIGH
LOW
Fiber Diameter
SMALL
Intermediate
LARGE
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Tetanic Contraction
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PCSA
(cm2)
=
Muscle Mass (g) · cosine Θ
ρ (g/cm3) · Fiber Length (cm)
Θ is the pennation angle of the muscle fibers
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Effects of Muscle Length and Contraction Velocity
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Muscles Respond to Loads
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Transduction of mechanical
load
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Forces transmitted through
extracellular matrix
Generate chemical signals
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Activate voltage gated channels
Activate IGF secretion (autocrine
signaling)
Transduction of neural
activation
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Ca2+ increase – activate Ca2+ calmodulin, calcineurin pathway
Alter gene expression in favor of
protein synthesis
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Protein Synthesis
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Protein Degradation
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Muscle Development and Maintenance
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Proliferate after heavy
use or muscle injury
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Tidball, J. Appl. Phsyiol., 2005
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Haszele and Price, Endocrinology, 2004.
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Interest in Myostatin
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Myostatin is a member of the TGF-b superfamily that
regulates development and tissue homeostasis;
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Myostatin is expressed almost exclusively in skeletal
muscle and acts as a negative regulator of muscle
growth;
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Rodent models of experimental disease states show
upregulated myostatin mRNA
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Studies in humans show that a lack of functional
myostatin results in increased muscle mass due to
hyperplasia and/or hypertrophy.
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TGFβ Superfamily
Se-Jin Lee, Annual Review Cell Dev Bio, 2004
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Myostatin Effects
Activation of
of
Activation
Myostatin
Myostatin Pathway
Pathway
Muscle Wasting /
Cachexia Syndrome
Myostatin Pathway
Blockade
Skeletal Muscle
Growth / Leanness
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Myostatin’s Obvious Effects
Naturally deficient
myostatin gene
Genetically created
deficient myostatin gene
(Knockout)
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Myostatin and Humans
But not just cattle and
mice …….
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Inhibition of the Myostatin Inhibitor
Se-Jin Lee, Annual Review Cell Dev Bio, 2004
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Myostatin Signaling
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Myostatin vs. Other Established Muscle
Metabolism Pathways
Mature Myocyte
IGF1
Myoblast
CdK2
CdK inhibitors
(p21)
Differentiation
Myogenesis
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MYOSTATIN
Phospho
SMAD2/3
Phospho
ActRIIb
PI3K/Akt
GSK3
mTOR
MyoD
MEF2
FOXO
eIF2B 4EBP1
S6K
Ubiquitin-Proteasome
Pathway
(Atrogin-1, MuRF-1)
PROTEIN
SYNTHESIS
PROTEIN (e.g. MHC)
DEGRADATION
?
+
-
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Potential for Blocking Myostatin
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Skeletal muscle wasting is prevalent in a variety of
diseases
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Weightlessness during space flight
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Cancer cachexia
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Muscular dystrophy
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Geriatric sarcopenia
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Obesity/diabetes
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Skeletal muscle wasting results in reduced muscle
strength, disability, and impaired quality of life;
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No current therapy to prevent or reverse muscle
atrophy.
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Disuse Models
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Suspended at 30º for 14 days
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Access to 100%
of cage
Food and water
ad libitum
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12-h photoperiod
Human bedrest (6º Head
Down Tilt)
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Durations - days to months
Cardiovascular, muscle and bone
effects
Controlled diet
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Hindlimb Suspension Effects
Muscle Mass
Soleus Wet Mass (mg)
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14
12
10
8
6
4
2
0
10.9
7.9
US P
TS P
Isolated Muscle
Strength
Whole Animal
Leg Strength
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Body Mass
27.00
26.50
US D
Body Mass (grams)
26.00
25.50
25.00
US P
24.50
TS D
24.00
23.50
TS P
23.00
22.50
22.00
0
2
4
6
8
10
12
14
Day of Study
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Lean Body Mass
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US > TS
P<0.001
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D>P
Lean Body Mass (g) .
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P<0.001
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18
17
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≈
0
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US P
US D
TS P
TS D
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Study Design
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Subjects – 10 male volunteers, 18-45 years old
10 day strict horizontal bed rest with restricted 5 day lead in
and 4 day follow up periods
Controlled diet – 55% carb, 30% fat, 15% protein
Caloric intake set to maintain body weight
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Double Threshold Analysis
Raw
Image
Partially
Processed
Image
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70
60
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Pre-Bed Rest
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End-Bed Rest
Δ Change Mean CSA (%)
Mean CSA / Slice (cm2)
Quadriceps Size Change
0%
p < 0.001
-2%
-4%
-5.0%
-6%
-8%
-10%
MRI images obtained with Tr = 550ms, Te = 10ms
Slice thickness = 1cm with 0 overlap
Pre-BR and end-BR slices aligned on anatomical features
Analysis from distal end of rectus femoris to highest
portion of thigh excluding the gluteus maximus
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GDF8 vs. Δ Muscle Size
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Correlation found between absolute level of GDF8
expression pre-bed rest with change in muscle size
Correlations between Δ muscle size and Δ myostatin
expression were not observed
Δ Quads Mean CSA (%)
Pre-BR GDF8/GAPDH
0%
-2%
-4%
0.0
1.0
2.0
3.0
4.0
r = - 0.66
p < 0.05
-6%
-8%
-10%
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Summary of Muscle Feedback
Circulating IGF-1
External
Loads /
Demands
Muscle
Strength
(PCSA)
Transduction
* Mechanical
* Electrical
IGF-1
+
Myostatin
Protein
Synthesis
Muscle
Hypertrophy
+
Muscle
Hyperplasia
Insulin
Protein
Degradation
Satellite Cell
Activation
-
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-
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