Holloway Tanya M, McGlory Chris, McKellar Sean, Morgan Adrienne, Hamill Mike, Afeyan Raffi, Comb William, Confer Scharmen, Zhao Peng, Hinton Mark, Kubassova Olga, Chakravarthy Manu V, Phillips Stuart M
Department of Kinesiology, McMaster University, Hamilton, ON, Canada.
Axcella Health, Inc., Cambridge, MA, United States.
Front Nutr. 2019 Jul 10;6:105. doi: 10.3389/fnut.2019.00105. eCollection 2019.
Skeletal muscle disuse leads to atrophy, declines in muscle function, and metabolic dysfunction that are often slow to recover. Strategies to mitigate these effects would be clinically relevant. In a double-blind randomized-controlled pilot trial, we examined the safety and tolerability as well as the atrophy mitigating effect of a novel amino acid composition (AXA2678), during single limb immobilization. Twenty healthy young men were randomly assigned (10 per group) to receive AXA2678 or an excipient- and energy-matched non-amino acid containing placebo (PL) for 28d: days 1-7, pre-immobilization; days 8-15, immobilization; and days 16-28 post-immobilization recovery. Muscle biopsies were taken on d1, d8 (immobilization start), d15 (immobilization end), and d28 (post-immobilization recovery). Magnetic resonance imaging (MRI) was utilized to assess quadriceps muscle volume (Mvol), muscle cross-sectional area (CSA), and muscle fat-fraction (FF: the fraction of muscle occupied by fat). Maximal voluntary leg isometric torque was assessed by dynamometry. Administration of AXA2678 attenuated muscle disuse atrophy compared to PL ( < 0.05) with changes from d8 to d15 in PL: ΔMvol = -2.4 ± 2.3% and ΔCSA = -3.1% ± 2.1%, both < 0.001 vs. zero; against AXA2678: ΔMvol: -0.7 ± 1.8% and ΔCSA: -0.7 ± 2.1%, both > 0.3 vs. zero; and < 0.05 between treatment conditions for CSA. During immobilization, muscle FF increased in PL but not in AXA2678 (PL: 12.8 ± 6.1%, AXA2678: 0.4 ± 3.1%; < 0.05). Immobilization resulted in similar reductions in peak leg isometric torque and change in time-to-peak (TTP) torque in both groups. Recovery (d15-d28) of peak torque and TTP torque was also not different between groups, but showed a trend for better recovery in the AXA2678 group. Thrice daily consumption of AXA2678 for 28d was found to be safe and well-tolerated. Additionally, AXA2678 attenuated atrophy, and attenuated accumulation of fat during short-term disuse. Further investigations on the administration of AXA2678 in conditions of muscle disuse are warranted. https://clinicaltrials.gov, identifier: NCT03267745.
骨骼肌废用会导致萎缩、肌肉功能下降和代谢功能障碍，而这些往往恢复缓慢。减轻这些影响的策略具有临床相关性。在一项双盲随机对照试验中，我们研究了一种新型氨基酸组合物（AXA2678）在单肢固定期间的安全性、耐受性以及减轻萎缩的效果。20名健康年轻男性被随机分配（每组10人）接受AXA2678或一种与赋形剂和能量匹配的不含氨基酸的安慰剂（PL），为期28天：第1 - 7天，固定前；第8 - 15天，固定期；第16 - 28天，固定后恢复期。在第1天、第8天（固定开始）、第15天（固定结束）和第28天（固定后恢复）进行肌肉活检。利用磁共振成像（MRI）评估股四头肌体积（Mvol）、肌肉横截面积（CSA）和肌肉脂肪分数（FF：肌肉中脂肪所占的比例）。通过测力计评估最大自主腿部等长扭矩。与PL相比，AXA2678给药减轻了肌肉废用性萎缩（<0.05），PL组从第8天到第15天的变化为：ΔMvol = -2.4 ± 2.3%，ΔCSA = -3.1% ± 2.1%，两者均<0.001对比零；与AXA2678组相比：ΔMvol：-0.7 ± 1.8%，ΔCSA：-0.7 ± 2.1%，两者均>0.3对比零；且两组间CSA的治疗情况差异<0.05。在固定期间，PL组肌肉FF增加，而AXA2678组未增加（PL组：12.8 ± 6.1%，AXA2678组：0.4 ± 3.1%；<0.05）。两组固定均导致腿部等长扭矩峰值和峰值时间（TTP）扭矩变化出现相似程度的降低。两组间峰值扭矩和TTP扭矩的恢复（第15 - 28天）也无差异，但AXA2678组显示出更好的恢复趋势。发现每日三次服用AXA2678，持续28天是安全且耐受性良好的。此外，AXA2678减轻了萎缩，并减轻了短期废用期间脂肪的积累。有必要对AXA2678在肌肉废用情况下的给药进行进一步研究。https://clinicaltrials.gov，标识符：NCT03267745 。
