Kim Yuho, Parry Hailey A, Willingham T Bradley, Alspaugh Greg, Lindberg Eric, Combs Christian A, Knutson Jay R, Bleck Christopher K E, Glancy Brian
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Department of Physical Therapy and Kinesiology, University of Massachusetts Lowell, Massachusetts, USA.
J Physiol. 2024 Mar;602(5):891-912. doi: 10.1113/JP285014. Epub 2024 Mar 1.
Skeletal muscle cellular development requires the integrated assembly of mitochondria and other organelles adjacent to the sarcomere in support of muscle contractile performance. However, it remains unclear how interactions among organelles and with the sarcomere relates to the development of muscle cell function. Here, we combine 3D volume electron microscopy, proteomic analyses, and live cell functional imaging to investigate the postnatal reorganization of mitochondria-organelle interactions in skeletal muscle. We show that while mitochondrial networks are disorganized and loosely associated with the contractile apparatus at birth, contact sites among mitochondria, lipid droplets and the sarcoplasmic reticulum are highly abundant in neonatal muscles. The maturation process is characterized by a transition to highly organized mitochondrial networks wrapped tightly around the muscle sarcomere but also to less frequent interactions with both lipid droplets and the sarcoplasmic reticulum. Concomitantly, expression of proteins involved in mitochondria-organelle membrane contact sites decreases during postnatal development in tandem with a decrease in abundance of proteins associated with sarcomere assembly despite an overall increase in contractile protein abundance. Functionally, parallel measures of mitochondrial membrane potential, NADH redox status, and NADH flux within intact cells revealed that mitochondria in adult skeletal muscle fibres maintain a more activated electron transport chain compared with neonatal muscle mitochondria. These data demonstrate a developmental redesign reflecting a shift from muscle cell assembly and frequent inter-organelle communication toward a muscle fibre with mitochondrial structure, interactions, composition and function specialized to support contractile function. KEY POINTS: Mitochondrial network organization is remodelled during skeletal muscle postnatal development. The mitochondrial outer membrane is in frequent contact with other organelles at birth and transitions to more close associations with the contractile apparatus in mature muscles. Mitochondrial energy metabolism becomes more activated during postnatal development. Understanding the developmental redesign process within skeletal muscle cells may help pinpoint specific areas of deficit in muscles with developmental disorders.
骨骼肌细胞的发育需要线粒体和其他与肌节相邻的细胞器进行整合组装，以支持肌肉的收缩性能。然而，细胞器之间以及与肌节的相互作用如何与肌肉细胞功能的发育相关仍不清楚。在这里，我们结合三维体积电子显微镜、蛋白质组学分析和活细胞功能成像，来研究骨骼肌中线粒体-细胞器相互作用的出生后重组。我们发现，虽然线粒体网络在出生时是无序的，并且与收缩装置松散相关，但线粒体、脂滴和肌浆网之间的接触位点在新生肌肉中非常丰富。成熟过程的特征是向紧密包裹在肌肉肌节周围的高度组织化线粒体网络转变，但与脂滴和肌浆网的相互作用也减少。与此同时，参与线粒体-细胞器膜接触位点的蛋白质表达在出生后发育过程中下降，同时与肌节组装相关的蛋白质丰度也下降，尽管收缩蛋白的丰度总体上有所增加。在功能上，对完整细胞中线粒体膜电位、NADH氧化还原状态和NADH通量的并行测量表明，与新生肌肉线粒体相比，成年骨骼肌纤维中的线粒体维持着更活跃的电子传递链。这些数据表明了一种发育上的重新设计，反映了从肌肉细胞组装和频繁的细胞器间通讯向具有专门支持收缩功能的线粒体结构、相互作用、组成和功能的肌纤维的转变。要点：线粒体网络组织在骨骼肌出生后发育过程中发生重塑。线粒体外膜在出生时与其他细胞器频繁接触，并在成熟肌肉中转变为与收缩装置更紧密的联系。线粒体能量代谢在出生后发育过程中变得更加活跃。了解骨骼肌细胞内的发育重新设计过程可能有助于确定发育障碍肌肉中特定的缺陷区域。
