Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, MA, 02139, USA.
Translational Medicine, Novartis Institutes for BioMedical Research, Basel, Switzerland.
J Cachexia Sarcopenia Muscle. 2017 Oct;8(5):727-734. doi: 10.1002/jcsm.12205. Epub 2017 Sep 14.
Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization.
In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study.
Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT: -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study.
A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint-immobilizing cast.
失用性萎缩的患者会经历急性骨骼肌质量丧失，随后导致力量和身体能力丧失。在这些患者中，尤其是老年人，即使改善营养和进行抗阻运动，完全恢复仍然是一个挑战。本研究旨在通过下肢固定的实验模型，探索靶向激活素 II 型受体的人单克隆抗体 bimagrumab 对恢复失用性萎缩骨骼肌体积的临床潜力。
在这项双盲、安慰剂对照试验中，健康年轻男性（n=24；平均年龄 24.1 岁）将一只下肢完全包裹在石膏中 2 周，以诱导失用性萎缩。拆除石膏后，受试者被随机分为单次静脉（i.v.）注射 bimagrumab 30mg/kg（n=15）或安慰剂（n=9）组，并随访 12 周。整个 12 周研究期间，评估了大腿肌肉体积（TMV）和大腿间肌内脂肪组织（IMAT）和皮下脂肪组织（SCAT）、最大自主膝关节伸展力量以及安全性的变化。
石膏固定导致 TMV 平均损失-4.8%，IMAT 和 SCAT 体积也相应增加。在拆除石膏后 2 周，bimagrumab 30mg/kg i.v. 迅速增加了 TMV，12 周时比预石膏水平增加了+5.1%。相比之下，安慰剂组在 12 周时 TMV 恢复到预石膏水平（-0.1%）。石膏固定腿的脂肪增加在安慰剂组持续存在，而 bimagrumab 组在第 12 周时显著减少（IMAT：-6.6%，SCAT：-3.5%）。所有受试者的石膏固定腿的膝关节伸展力量下降了约 25%，在拆除石膏后 6 周内恢复到预石膏水平。bimagrumab 耐受性良好，在研究期间未报告严重或严重不良事件。
单次静脉注射 30mg/kg 的 bimagrumab 可安全加速关节固定 2 周后的 TMV 恢复和累积 IMAT 的逆转。
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