Bioreactor development for skeletal muscle hypertrophy and atrophy by manipulating uniaxial cyclic strain: proof of concept.

IF 4.4 1区 物理与天体物理 Q1 MULTIDISCIPLINARY SCIENCES npj Microgravity Pub Date : 2024-06-11 DOI:10.1038/s41526-023-00320-0
Khaled Y Kamal, Mariam Atef Othman, Joo-Hyun Kim, John M Lawler
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Abstract

Skeletal muscles overcome terrestrial, gravitational loading by producing tensile forces that produce movement through joint rotation. Conversely, the microgravity of spaceflight reduces tensile loads in working skeletal muscles, causing an adaptive muscle atrophy. Unfortunately, the design of stable, physiological bioreactors to model skeletal muscle tensile loading during spaceflight experiments remains challenging. Here, we tested a bioreactor that uses initiation and cessation of cyclic, tensile strain to induce hypertrophy and atrophy, respectively, in murine lineage (C2C12) skeletal muscle myotubes. Uniaxial cyclic stretch of myotubes was conducted using a StrexCell® (STB-1400) stepper motor system (0.75 Hz, 12% strain, 60 min day^-1). Myotube groups were assigned as follows: (a) quiescent over 2- or (b) 5-day (no stretch), (c) experienced 2-days (2dHY) or (d) 5-days (5dHY) of cyclic stretch, or (e) 2-days of cyclic stretch followed by a 3-day cessation of stretch (3dAT). Using ß-sarcoglycan as a sarcolemmal marker, mean myotube diameter increased significantly following 2dAT (51%) and 5dAT (94%) vs. matched controls. The hypertrophic, anabolic markers talin and Akt phosphorylation (Thr308) were elevated with 2dHY but not in 3dAT myotubes. Inflammatory, catabolic markers IL-1ß, IL6, and NF-kappaB p65 subunit were significantly higher in the 3dAT group vs. all other groups. The ratio of phosphorylated FoxO3a/total FoxO3a was significantly lower in 3dAT than in the 2dHY group, consistent with elevated catabolic signaling during unloading. In summary, we demonstrated proof-of-concept for a spaceflight research bioreactor, using uniaxial cyclic stretch to produce myotube hypertrophy with increased tensile loading, and myotube atrophy with subsequent cessation of stretch.

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通过操纵单轴循环应变开发骨骼肌肥大和萎缩的生物反应器:概念验证。
骨骼肌通过产生拉力来克服地面重力负荷,从而通过关节旋转产生运动。相反,太空飞行的微重力降低了工作骨骼肌的拉伸负荷,导致肌肉适应性萎缩。遗憾的是,设计稳定的生理生物反应器来模拟太空飞行实验中的骨骼肌拉伸负荷仍然具有挑战性。在这里,我们测试了一种生物反应器,利用启动和停止循环拉伸应变分别诱导小鼠系(C2C12)骨骼肌肌管肥大和萎缩。使用 StrexCell® (STB-1400) 步进电机系统对肌管进行单轴循环拉伸(0.75 Hz、12%应变、60 分钟/天^-1)。肌管组分配如下(a)静止 2 天或(b)5 天(无拉伸),(c)经历 2 天(2dHY)或(d)5 天(5dHY)循环拉伸,或(e)2 天循环拉伸后 3 天停止拉伸(3dAT)。使用 ß-sarcoglycan 作为肌浆标志物,与匹配的对照组相比,2dAT(51%)和 5dAT(94%)后平均肌管直径显著增加。肥大、合成代谢标志物塔林和 Akt 磷酸化(Thr308)在 2dHY 中升高,但在 3dAT 肌管中没有升高。与所有其他组相比,3dAT 组的炎症、代谢标志物 IL-1ß、IL6 和 NF-kappaB p65 亚基显著升高。磷酸化 FoxO3a 与总 FoxO3a 之比,3dAT 组明显低于 2dHY 组,这与卸载期间分解代谢信号升高一致。总之,我们证明了太空飞行研究生物反应器的概念验证,即利用单轴循环拉伸,在拉伸负荷增加时产生肌管肥大,在随后拉伸停止时产生肌管萎缩。
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来源期刊
npj Microgravity
npj Microgravity Physics and Astronomy-Physics and Astronomy (miscellaneous)
CiteScore
7.30
自引率
7.80%
发文量
50
审稿时长
9 weeks
期刊介绍: A new open access, online-only, multidisciplinary research journal, npj Microgravity is dedicated to publishing the most important scientific advances in the life sciences, physical sciences, and engineering fields that are facilitated by spaceflight and analogue platforms.
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