Inherited fatty acid oxidation diseases in their mild forms often present as metabolic myopathies. Carnitine Palmitoyl Transferase 2 (CPT2) deficiency, one such prototypical disorder is associated with compromised myotube differentiation. Here, we show that CPT2-deficient myotubes exhibit defects in focal adhesions and redox balance, exemplified by increased SOD2 expression. We document unprecedented alterations in the cellular prion protein PrP^C, which directly arise from the failure in CPT2 enzymatic activity. We also demonstrate that the loss of PrP^C function in normal myotubes recapitulates the defects in focal adhesion, redox balance and differentiation hallmarks monitored in CPT2-deficient cells. These results are further corroborated by studies performed in muscles from Prnp^−/− mice. Altogether, our results unveil a molecular scenario, whereby PrP^C dysfunction governed by faulty CPT2 activity may drive aberrant focal adhesion turnover and hinder proper myotube differentiation. Our study adds a novel facet to the involvement of PrP^C in diverse physiopathological situations.

轻度遗传的脂肪酸氧化疾病通常表现为代谢性肌病。肉碱棕榈酰转移酶2（CPT2）缺乏是一种此类原型疾病，与肌管分化受损有关。在这里，我们表明缺乏CPT2的肌管在粘着斑和氧化还原平衡中表现出缺陷，这可以通过增加SOD2表达来体现。我们记录了细胞病毒蛋白PrP ^C的空前变化，这直接源于CPT2酶活性的失败。我们还证明，正常肌管中PrP ^C功能的丧失概括了CPT2缺陷细胞中监测的粘着斑，氧化还原平衡和分化标志的缺陷。这些结果进一步证实了对肌肉的研究。Prnp ^-/-小鼠。总而言之，我们的结果揭示了一种分子场景，其中由错误的CPT2活性控制的PrP ^C功能障碍可能会驱动异常的粘着粘连更新并阻碍正常的肌管分化。我们的研究为PrP ^C在多种生理病理情况中的参与增添了新的面貌。