Electrical stimulation increases hypertrophy and metabolic flux in tissue-engineered human skeletal muscle.
Electrical stimulation increases hypertrophy and metabolic flux in tissue-engineered human skeletal muscle.
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电刺激会增加组织工程的人骨骼肌的肥大和代谢通量。
DOI：
10.1016/j.biomaterials.2018.08.058
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发表时间：
2019-04
期刊：
影响因子：
14
通讯作者：
Bursac N
中科院分区：
文献类型：
--
作者：
Khodabukus A;Madden L;Prabhu NK;Koves TR;Jackman CP;Muoio DM;Bursac N
可收缩人类骨骼肌的体外模型有望用于疾病建模和药物开发，但与天然成人肌肉相比，其特性尚不成熟。为了解决这一限制，使用1Hz和10Hz的间歇性刺激方案对3D组织工程人体肌肉（肌束）进行电刺激。肌管中的肌营养不良蛋白表现出成熟的膜定位，表明相对较早的开始发育成熟。一周的刺激显著增加了肌束大小、肌肉蛋白丰度、钙瞬态振幅（~2倍）和强直力（~3倍），导致迄今为止报道的工程化人类肌肉产生的最高比力（19.3mN/mm2）。与1Hz电刺激相比，10Hz电刺激方案导致更大的肌管肥大和上调mTORC1和ERK1/2活性。与未改变糖酵解或线粒体蛋白水平的对照肌束相比，电刺激的肌束抗疲劳能力也有所下降。受刺激的肌束中葡萄糖消耗增加和乙酰肉碱丰度降低表明糖酵解和脂肪酸代谢通量增加。此外，电刺激肌束导致代谢向长链脂肪酸氧化转变，这可以从中、长链酰基肉碱丰度的增加中看出。综上所述，我们的研究提供了一种先进的体外人类骨骼肌模型，其结构、功能、成熟度和代谢通量都有所改善。
In vitro models of contractile human skeletal muscle hold promise for use in disease modeling and drug development, but exhibit immature properties compared to native adult muscle. To address this limitation, 3D tissue-engineered human muscles (myobundles) were electrically stimulated using intermittent stimulation regimes at 1Hz and 10Hz rate. Dystrophin in myotubes exhibited mature membrane localization suggesting a relatively advanced starting developmental maturation. One-week stimulation significantly increased myobundle size, sarcomeric protein abundance, calcium transient amplitude (~2-fold), and tetanic force (~3-fold) resulting in the highest specific force generation (19.3mN/mm2) reported for engineered human muscles to date. Compared to 1Hz electrical stimulation, the 10Hz stimulation protocol resulted in greater myotube hypertrophy and upregulated mTORC1 and ERK1/2 activity. Electrically stimulated myobundles also showed a decrease in fatigue resistance compared to control myobundles without changes in glycolytic or mitochondrial protein levels. Greater glucose consumption and decreased abundance of acetylcarnitine in stimulated myobundles indicated increased glycolytic and fatty acid metabolic flux. Moreover, electrical stimulation of myobundles resulted in a metabolic shift towards longer-chain fatty acid oxidation as evident from increased abundances of medium- and long-chain acylcarnitines. Taken together, our study provides an advanced in vitro model of human skeletal muscle with improved structure, function, maturation, and metabolic flux.
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