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

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.