Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Nat Commun. 2017 Apr 28;8:15153. doi: 10.1038/ncomms15153.
Growth and differentiation factor 8 (GDF8) is a TGF-β superfamily member, and negative regulator of skeletal muscle mass. GDF8 inhibition results in prominent muscle growth in mice, but less impressive hypertrophy in primates, including man. Broad TGF-β inhibition suggests another family member negatively regulates muscle mass, and its blockade enhances muscle growth seen with GDF8-specific inhibition. Here we show that activin A is the long-sought second negative muscle regulator. Activin A specific inhibition, on top of GDF8 inhibition, leads to pronounced muscle hypertrophy and force production in mice and monkeys. Inhibition of these two ligands mimics the hypertrophy seen with broad TGF-β blockers, while avoiding the adverse effects due to inhibition of multiple family members. Altogether, we identify activin A as a second negative regulator of muscle mass, and suggest that inhibition of both ligands provides a preferred therapeutic approach, which maximizes the benefit:risk ratio for muscle diseases in man.
生长分化因子 8（GDF8）是 TGF-β 超家族的一员，也是骨骼肌质量的负调控因子。GDF8 的抑制导致小鼠肌肉明显生长，但在包括人类在内的灵长类动物中，肌肉肥大的效果不那么明显。广泛的 TGF-β 抑制表明另一个家族成员负调控肌肉质量，其阻断作用增强了 GDF8 特异性抑制所观察到的肌肉生长。在这里，我们表明激活素 A 是长期以来寻求的第二种负向肌肉调节因子。在 GDF8 抑制的基础上，激活素 A 的特异性抑制导致小鼠和猴子的肌肉明显肥大和力量产生。这两种配体的抑制模拟了广泛的 TGF-β 阻滞剂所观察到的肥大，同时避免了由于抑制多个家族成员而产生的不良反应。总之，我们确定激活素 A 是肌肉质量的第二种负调控因子，并表明抑制这两种配体提供了一种首选的治疗方法，最大限度地提高了人类肌肉疾病的获益：风险比。
