Coordinated cytoskeleton-mitochondria organization during myogenesis is crucial for muscle development and function. Our understanding of the underlying regulatory mechanisms remains inadequate. Here, we identified a novel muscle-enriched protein, PRR33, which is upregulated during myogenesis and acts as a promyogenic factor. Depletion of Prr33 in C2C12 represses myoblast differentiation. Genetic deletion of Prr33 in mice reduces myofiber size and decreases muscle strength. The Prr33 mutant mice also exhibit impaired myogenesis and defects in muscle regeneration in response to injury. Interactome and transcriptome analyses reveal that PRR33 regulates cytoskeleton and mitochondrial function. Remarkably, PRR33 interacts with DESMIN, a key regulator of cytoskeleton-mitochondria organization in muscle cells. Abrogation of PRR33 in myocytes substantially abolishes the interaction of DESMIN filaments with mitochondria, leading to abnormal intracellular accumulation of DESMIN and mitochondrial disorganization/dysfunction in myofibers. Together, our findings demonstrate that PRR33 and DESMIN constitute an important regulatory module coordinating mitochondrial organization with muscle differentiation.

肌发生过程中协调的细胞骨架-线粒体组织对于肌肉的发育和功能至关重要。我们对潜在监管机制的理解仍然不够。在这里，我们鉴定了一种新型的肌肉富集蛋白 PRR33，它在肌生成过程中上调并充当促肌生成因子。 C2C12 中Prr33的缺失会抑制成肌细胞分化。小鼠中Prr33的基因缺失会减少肌纤维尺寸并降低肌肉强度。 Prr33突变小鼠还表现出肌生成受损和损伤后肌肉再生缺陷。相互作用组和转录组分析表明 PRR33 调节细胞骨架和线粒体功能。值得注意的是，PRR33 与 DESMIN 相互作用，DESMIN 是肌肉细胞中细胞骨架-线粒体组织的关键调节因子。消除肌细胞中的 PRR33 基本上消除了 DESMIN 丝与线粒体的相互作用，导致 DESMIN 异常细胞内积累和肌纤维中的线粒体解体/功能障碍。总之，我们的研究结果表明 PRR33 和 DESMIN 构成了协调线粒体组织与肌肉分化的重要调节模块。