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线粒体分裂抑制剂 1(mdivi-1)可增加工程化骨骼肌产生的氧化能力和收缩应激。

Mitochondrial division inhibitor 1 (mdivi-1) increases oxidative capacity and contractile stress generated by engineered skeletal muscle.

机构信息

Laboratory for Living Systems Engineering, Department of Biomedical Engineering, USC Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.

Smidt Heart Institute and Barbra Streisand Women's Heart Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

出版信息

FASEB J. 2020 Sep;34(9):11562-11576. doi: 10.1096/fj.201901039RR. Epub 2020 Jul 11.

Abstract

In skeletal muscle fibers, mitochondria are densely packed adjacent to myofibrils because adenosine triphosphate (ATP) is needed to fuel sarcomere shortening. However, despite this close physical and biochemical relationship, the effects of mitochondrial dynamics on skeletal muscle contractility are poorly understood. In this study, we analyzed the effects of Mitochondrial Division Inhibitor 1 (mdivi-1), an inhibitor of mitochondrial fission, on the structure and function of both mitochondria and myofibrils in skeletal muscle tissues engineered on micromolded gelatin hydrogels. Treatment with mdivi-1 did not alter myotube morphology, but did increase the mitochondrial turbidity and oxidative capacity, consistent with reduced mitochondrial fission. Mdivi-1 also significantly increased basal, twitch, and tetanus stresses, as measured using the Muscular Thin Film (MTF) assay. Finally, mdivi-1 increased sarcomere length, potentially due to mdivi-1-induced changes in mitochondrial volume and compression of myofibrils. Together, these results suggest that mdivi-1 increases contractile stress generation, which may be caused by an increase in maximal respiration and/or sarcomere length due to increased volume of individual mitochondria. These data reinforce that mitochondria have both biochemical and biomechanical roles in skeletal muscle and that mitochondrial dynamics can be manipulated to alter muscle contractility.

摘要

在骨骼肌纤维中,线粒体与肌原纤维紧密相邻排列,因为三磷酸腺苷(ATP)是肌节缩短的燃料。然而,尽管存在这种紧密的物理和生化关系,但线粒体动力学对骨骼肌收缩性的影响仍知之甚少。在这项研究中,我们分析了线粒体分裂抑制剂 1(mdivi-1)对微模铸明胶水凝胶工程化骨骼肌组织中线粒体和肌原纤维结构和功能的影响。mdivi-1 处理不会改变肌管形态,但会增加线粒体混浊度和氧化能力,这与线粒体分裂减少一致。mdivi-1 还显著增加了基础、抽搐和强直应激,如使用肌肉薄膜(MTF)测定法所测量的那样。最后,mdivi-1 增加了肌节长度,这可能是由于 mdivi-1 引起的线粒体体积变化和肌原纤维压缩所致。总之,这些结果表明,mdivi-1 增加了收缩应激的产生,这可能是由于单个线粒体体积增加导致最大呼吸和/或肌节长度增加所致。这些数据强化了线粒体在骨骼肌中具有生化和生物力学作用,并且可以操纵线粒体动力学来改变肌肉收缩性。

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