Transcript No Slide Title

Biochem 230: 25 Oct 2004
Intervention
Myostatin
Muscle Growth
Some less noble applications …
Super TGF
Myostatin and TGFß signaling
Inhibition of muscle growth
JA16 antibodies inhibit TGFß
pathway in cultured cells
11.5 µL / mL
Switch to in vivo . . .
• mdx mice widely used: availability, cost, generation time
• but not an ideal phenocopy of MD in humans:
- relatively mild phenotype
- histologically normal muscle at birth
- necrosis begins in week 3, continues for about 1 month
- regeneration compensates for muscle damage
- mdx muscle does not resemble advanced MD
Are myostatin-associated effects dependent
on mdx mouse context?
Anti-myostatin associated
increases in body weight
n=12
P < 0.03
(t-test)
1 month old mice
60 mg/kg antibody weekly for three months
Anti-myostatin associated with
metabolic increase and strength
Indirect calorimetry - Oxymax Equalflow system
n = 4, p < 0.01
Increased caloric output
“consistent with an
increase in muscle mass
and body size”
n = 6, p < 0.002
Increased rota-rod time
“consistent with increased
functional muscle mass
and intact neuromuscular
coordination”
Whole body
muscle strength,
endurance
Physiological and morphometric comparisons of
EDL in treated vs. control mice
EDL: extensor digitorum longus
CSA: cross-sectional area
ECC: eccentric contraction
(measures damage and damage
recovery)
CNF: centrally-nucleated fiber regeneration or change in progenitor
cell commitment
Anti-myostatin associated increases
in muscle mass and strength
n = 12, p < 0.0001
n = 12, p < 0.03
n = 12, p < 0.014
n = 12, p < 0.003
Hypertrophy at single fibre level
“…overall shift of distribution towards larger areas [of single fibres]”
Decrease in degenerative changes and cellular
infiltration in diaphragms of treated mdx mice
Utrophin-independence and biochemical
evidence for improvement in treated mdx mice
Improvement in treated mdx mice
independent of utrophin
n = 6, p < 0.005
Outlook
• Improvement of dystrophic phenotype in mdx mice
by anatomical, physiological, and biochemical criteria
• Not all dystrophic changes helped: susceptibility to
damage by lengthening contractions not improved
• Proposed treatment for MD or other causes of
muscle loss (aging, infections, immobilization, disease)
• Relatively simple compared with gene or cell based
therapies
• Low toxicity concerns.