biochem 230: 25 oct 2004
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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 . . . . - PowerPoint PPT PresentationTRANSCRIPT
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 MDAre myostatin-associated effects dependent
on mdx mouse context?
Anti-myostatin associated increases in body weight
1 month old mice60 mg/kg antibody weekly for three months
n=12P < 0.03(t-test)
Whole body muscle strength,
endurance Increased caloric output “consistent with an
increase in muscle mass and body size”
Increased rota-rod time “consistent with
increased functional muscle mass and intact
neuromuscular coordination”
n = 4, p < 0.01 n = 6, p < 0.002
Indirect calorimetry - Oxymax Equalflow system
Anti-myostatin associated with metabolic increase and strength
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
strengthn = 12, p < 0.0001n = 12, p < 0.014
n = 12, p < 0.03 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.