Sarcopenia, a prevalent muscle disease characterized by muscle mass and strength reduction, is associated with impaired skeletal muscle regeneration. However, the influence of the biomechanical properties of sarcopenic skeletal muscle on the efficiency of the myogenic program remains unclear. Herein, we established a mouse model of sarcopenia and observed a reduction in stiffness within the sarcopenic skeletal muscle . To investigate whether the biomechanical properties of skeletal muscle directly impact the myogenic program, we established an in vitro system to explore the intrinsic mechanism involving matrix stiffness control of myogenic differentiation. Our findings identify the microtubule motor protein, kinesin-1, as a mechano-transduction hub that senses and responds to matrix stiffness, crucial for myogenic differentiation and muscle regeneration. Specifically, kinesin-1 activity is positively regulated by stiff matrices, facilitating its role in transporting mitochondria and enhancing translocation of the glucose transporter GLUT4 to the cell surface for glucose uptake. Conversely, the softer matrices significantly suppress kinesin-1 activity, leading to the accumulation of mitochondria around nuclei and hindering glucose uptake by inhibiting GLUT4 membrane translocation, consequently impairing myogenic differentiation. The insights gained from the system highlight the mechano-transduction significance of kinesin-1 motor proteins in myogenic differentiation. Furthermore, our study confirms that enhancing kinesin-1 activity in the sarcopenic mouse model restores satellite cell expansion, myogenic differentiation, and muscle regeneration. Taken together, our findings provide a potential target for improving muscle regeneration in sarcopenia.

中文翻译：

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基质力学通过调节驱动蛋白-1 活性来调节肌肉再生

肌肉减少症是一种常见的肌肉疾病，其特征是肌肉质量和力量减少，与骨骼肌再生受损有关。然而，少肌骨骼肌的生物力学特性对生​​肌程序效率的影响仍不清楚。在此，我们建立了肌肉减少症的小鼠模型，并观察到肌肉减少症骨骼肌内的硬度降低。为了研究骨骼肌的生物力学特性是否直接影响生肌程序，我们建立了体外系统来探索涉及生肌分化的基质刚度控制的内在机制。我们的研究结果表明，微管运动蛋白 kinesin-1 是一种机械传导中枢，可以感知基质硬度并做出反应，这对于肌源性分化和肌肉再生至关重要。具体来说，kinesin-1 活性受到刚性基质的正向调节，促进其在运输线粒体中的作用，并增强葡萄糖转运蛋白 GLUT4 易位至细胞表面以摄取葡萄糖。相反，较软的基质显着抑制驱动蛋白-1 活性，导致线粒体在细胞核周围积聚，并通过抑制 GLUT4 膜易位阻碍葡萄糖摄取，从而损害肌原性分化。从该系统获得的见解强调了驱动蛋白-1 运动蛋白在肌原分化中的机械转导重要性。此外，我们的研究证实，增强肌肉减少症小鼠模型中的驱动蛋白-1 活性可以恢复卫星细胞扩张、肌原性分化和肌肉再生。总而言之，我们的研究结果为改善肌肉减少症的肌肉再生提供了潜在的目标。