Myostatin as a Potential Target for Treatment of Muscle Contractures 

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Marianne Emmert
Qingnian Goh


By Marianne Emmert, Medical Sciences

Advisor: Qingnian Goh

Presentation ID: 314

Abstract: Injury to the brachial plexus at birth (Neonatal Brachial Plexus Injury - NBPI) is the most common cause of upper limb paralysis in children, occurring in approximately 1.5 of every 1,000 live births. It leads to the formation of secondary muscle contractures, or limb stiffness, which are disabling and incurable. Current strategies are insufficient in restoring muscle function and joint range of motion once contractures have developed. Using a mouse model of NBPI, we previously discovered that contractures result from impaired longitudinal muscle growth. This deficit in muscle length is mediated by increased levels of proteasome-mediated protein degradation in the denervated muscle, as inhibition of the proteasome markedly reduces contracture development. However, this novel pharmacologic strategy cannot be easily translated to humans. Prolonged administration of proteasome inhibitors results in potential cumulative toxicity as this drug nonspecifically blocks degradation and causes tissue damage to many organs, including the brain. As a result, our lab seeks to identify safer strategies to prevent contracture development by targeting muscle-specific regulators of the balance between protein degradation and synthesis. One such signaling pathway specific to skeletal muscle is the myostatin pathway. Myostatin is a negative regulator of protein balance. We hypothesize that neonatal denervation induces contractures through myostatin-dependent impairment of postnatal longitudinal muscle growth. To test this, we administered different dosages of the myostatin inhibitor (ACVR2B-Fc) to mice with surgically induced contractures. Our results showed a sex-specific response to myostatin inhibition, given that weekly dosage of ACV2RB-Fc is effective in reducing contracture severity in female mice.

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Category: New Frontiers