Cellular prion protein dysfunction in a prototypical inherited metabolic myopathy
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Cellular prion protein dysfunction in a prototypical inherited metabolic myopathy Fatima‑Zohra Boufroura1 · Céline Tomkiewicz‑Raulet2 · Virginie Poindessous1 · Johan Castille3 · Jean‑Luc Vilotte3 · Jean Bastin1 · Sophie Mouillet‑Richard1 · Fatima Djouadi1 Received: 11 May 2020 / Revised: 10 August 2020 / Accepted: 18 August 2020 © Springer Nature Switzerland AG 2020
Abstract 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 P rPC, which directly arise from the C failure in CPT2 enzymatic activity. We also demonstrate that the loss of P rP 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 PrPC 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 PrPC in diverse physiopathological situations. Keywords Inherited metabolic myopathy · Cellular prion protein · Muscle differentiation · Inherited fatty acid oxidation disorders · Focal adhesions · Redox balance
Introduction
Sophie Mouillet-Richard and Fatima Djouadi are co-senior authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03624-6) contains supplementary material, which is available to authorized users. * Sophie Mouillet‑Richard sophie.mouillet‑[email protected] * Fatima Djouadi [email protected] 1
Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université de Paris, 15, rue de L’Ecole de Médecine, 75006 Paris, France
2
Centre Universitaire des Saints Pères, INSERM U1124, Sorbonne Université, Université de Paris, 75006 Paris, France
3
Université Paris-Saclay, INRAE AgroParisTech, UMR1313 Génétique Animale et Biologie Intégrative, 78350 Jouy‑en‑Josas, France
Skeletal muscle dysfunction represents a frequent hallmark of inborn metabolic disorders [1]. One prototypical metabolic myopathy is the deficiency in Carnitine Palmitoyl Transferase 2 (CPT2), one of the most common inherited fatty acid oxidation (FAO) disorders. Until recently, the pathophysiological mechanisms underlying skeletal muscle defects in CPT2-deficient patients had remained enigmatic. Taking advantage of a unique collection of myoblasts from CPT2-deficient patients harboring “mild” mutations, associated with residual enzyme activity and responsible for the
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