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.

轻度的遗传性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) 缺乏症是一种典型疾病，与肌管分化受损有关。在这里，我们发现 CPT2 缺陷的肌管在粘着斑和氧化还原平衡方面表现出缺陷，例如 SOD2 表达增加。我们记录了细胞朊病毒蛋白 PrP ^C发生前所未有的变化，这种变化直接源于 CPT2 酶活性的失败。我们还证明，正常肌管中 PrP ^C功能的丧失重现了 CPT2 缺陷细胞中监测到的粘着斑、氧化还原平衡和分化标志的缺陷。这些结果得到了对Prnp ^−/−小鼠肌肉进行的研究的进一步证实。总而言之，我们的结果揭示了一种分子情况，即由错误的 CPT2 活性控制的 PrP ^C功能障碍可能会导致异常的粘着斑周转并阻碍适当的肌管分化。我们的研究为 PrP ^C在不同的病理生理学情况中的参与增加了一个新的方面。