A new AMPK activator, GSK773, corrects fatty acid oxidation and differentiation defect in CPT2-deficient myotubes - Archive ouverte HAL Access content directly
Journal Articles Human Molecular Genetics Year : 2018

A new AMPK activator, GSK773, corrects fatty acid oxidation and differentiation defect in CPT2-deficient myotubes

(1) , (1) , (1) , (2) , (2) , (3) , (3) , (4) , (5) , (1) , (1)
1
2
3
4
5

Abstract

Carnitine palmitoyl transferase 2 (CPT2) deficiency is one of the most common inherited fatty acid oxidation (FAO) defects and represents a prototypical mitochondrial metabolic myopathy. Recent studies have suggested a pivotal role of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle plasticity and mitochondrial homeostasis. Thus, we tested the potential of GSK773, a novel direct AMPK activator, to improve or correct FAO capacities in muscle cells from patients harboring various mutations. We used controls' and patients' myotubes and studied the parameters of FAO metabolism, of mitochondrial quantity and quality and of differentiation. We found that AMPK is constitutively activated in patients' myotubes, which exhibit both reduced FAO and impaired differentiation. GSK773 improves or corrects several metabolic hallmarks of CPT2 deficiency (deficient FAO flux and C16-acylcarnitine accumulation) by upregulating the expression of CPT2 protein. Beneficial effects of GSK773 are also likely due to stimulation of mitochondrial biogenesis and induction of mitochondrial fusion, by decreasing dynamin-related protein 1 and increasing mitofusin 2. GSK773 also induces a shift in myosin heavy chain isoforms toward the slow oxidative type and, therefore, fully corrects the differentiation process. We establish, through small interfering RNA knockdowns and pharmacological approaches, that these GSK773 effects are mediated through peroxisome proliferator-activated receptor gamma co-activator 1-alpha, reactive oxygen species and p38 mitogen-activated protein kinase, all key players of skeletal muscle plasticity. GSK773 recapitulates several important features of skeletal muscle adaptation to exercise. The results show that AMPK activation by GSK773 evokes the slow, oxidative myogenic program and triggers beneficial phenotypic adaptations in FAO-deficient myotubes. Thus, GSK773 might have therapeutic potential for correction of CPT2 deficiency.
Fichier principal
Vignette du fichier
Boufroura et al pour dépot HAL.pdf (11.56 Mo) Télécharger le fichier
Origin : Files produced by the author(s)
Loading...

Dates and versions

inserm-02894027 , version 1 (08-07-2020)
inserm-02894027 , version 2 (10-07-2020)

Identifiers

Cite

Fatima-Zohra Boufroura, Carole Le Bachelier, Céline Tomkiewicz-Raulet, Dimitri Schlemmer, Jean-François Benoist, et al.. A new AMPK activator, GSK773, corrects fatty acid oxidation and differentiation defect in CPT2-deficient myotubes. Human Molecular Genetics, 2018, 27 (19), pp.3417-3433. ⟨10.1093/hmg/ddy254⟩. ⟨inserm-02894027v2⟩
105 View
66 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More