1. Biochem 230: 25 Oct 2004

2. Intervention Myostatin Muscle Growth

3. Some less noble applications … Super TGF

4. Myostatin and TGFß signaling Inhibition of muscle growth

5. JA16 antibodies inhibit TGFß pathway in cultured cells 11.5 µL / mL

6. 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?

7. Anti-myostatin associated increases in body weight 1 month old mice 60 mg/kg antibody weekly for three months n=12 P < 0.03 (t-test)

8. 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 < 0.01n = 6, p < 0.002 Indirect calorimetry - Oxymax Equalflow system Anti-myostatin associated with metabolic increase and strength

9. 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

10. Anti-myostatin associated increases in muscle mass and strength n = 12, p < 0.0001n = 12, p < 0.014 n = 12, p < 0.03n = 12, p < 0.003

11. Hypertrophy at single fibre level “…overall shift of distribution towards larger areas [of single fibres]”

12. Decrease in degenerative changes and cellular infiltration in diaphragms of treated mdx mice

13. Utrophin-independence and biochemical evidence for improvement in treated mdx mice Improvement in treated mdx mice independent of utrophin n = 6, p < 0.005

14. 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.