Activin A more prominently regulates muscle mass in primates than does GDF8

Area of Science:

• Muscle biology
• Skeletal muscle physiology
• TGF-β superfamily signaling

Background:

• Growth differentiation factor 8 (GDF8) negatively regulates skeletal muscle mass.
• GDF8 inhibition causes muscle growth in mice but limited hypertrophy in primates.
• Broad TGF-β inhibition suggests another negative regulator of muscle mass exists.

Purpose of the Study:

• To identify the second negative regulator of muscle mass.
• To investigate the combined effect of inhibiting GDF8 and the identified regulator on muscle growth.

Main Methods:

• Investigated the role of activin A as a negative regulator of muscle mass.
• Administered specific inhibitors for GDF8 and activin A in mice and monkeys.
• Assessed muscle hypertrophy and force production.

Main Results:

• Identified activin A as the second negative regulator of muscle mass.
• Combined inhibition of GDF8 and activin A resulted in pronounced muscle hypertrophy and increased force production in mice and monkeys.
• This dual inhibition strategy mimicked broad TGF-β blockade effects without its adverse effects.

Conclusions:

• Activin A is a crucial negative regulator of skeletal muscle mass.
• Simultaneous inhibition of GDF8 and activin A represents a promising therapeutic strategy for muscle diseases.
• This approach offers an improved benefit:risk ratio for treating muscle wasting conditions in humans.