RT Journal Article
T1 Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle
A1 Hernández Camacho, Juan Diego
A1 Moreno Fernández-Ayala, Daniel José
A1 Vicente-García, Cristina
A1 Navas-Enamorado, Ignacio
A1 López-Lluch, Guillermo
A1 Oliva, Clara
A1 Artuch, Rafael
A1 Garcia-Villoria, Judith
A1 Ribes, Antonia
A1 de Cabo, Rafael
A1 Carvajal, Jaime
A1 Navas, Plácido
K1 Mitochondria
K1 Coenzyme Q
K1 Food deprivation
K1 Metabolism
K1 Fatty acids
AB ADCK2 haploinsufficiency-mediated mitochondrial coenzyme Q deficiency in skeletal muscle causes mitochondrial myopathy associated with defects in beta-oxidation of fatty acids, aged-matched metabolic reprogramming, and defective physical performance. Calorie restriction has proven to increase lifespan and delay the onset of chronic diseases associated to aging. To study the possible treatment by food deprivation, heterozygous Adck2 knockout mice were fed under 40% calorie restriction (CR) and the phenotype was followed for 7 months. The overall glucose and fatty acids metabolism in muscle was restored in mutant mice to WT levels after CR. CR modulated the skeletal muscle metabolic profile of mutant mice, partially rescuing the profile of WT animals. The analysis of mitochondria isolated from skeletal muscle demonstrated that CR increased both CoQ levels and oxygen consumption rate (OCR) based on both glucose and fatty acids substrates, along with mitochondrial mass. The elevated aerobic metabolism fits with an increase of type IIa fibers, and a reduction of type IIx in mutant muscles, reaching WT levels. To further explore the effect of CR over muscle stem cells, satellite cells were isolated and induced to differentiate in culture media containing serum from animals in either ad libitum or CR diets for 72 h. Mutant cells showed slower differentiation alongside with decreased oxygen consumption. In vitro differentiation of mutant cells was increased under CR serum reaching levels of WT isolated cells, recovering respiration measured by OCR and partially beta-oxidation of fatty acids. The overall increase of skeletal muscle bioenergetics following CR intervention is paralleled with a physical activity improvement, with some increases in two and four limbs strength tests, and weights strength test. Running wheel activity was also partially improved in mutant mice under CR. These results demonstrate that CR intervention, which has been shown to improve age-associated physical and metabolic decline in WT mice, also recovers the defective aerobic metabolism and differentiation of skeletal muscle in mice caused by ADCK2 haploinsufficiency.
PB Frontiers Media
YR 2022
FD 2022
LK https://hdl.handle.net/10433/19960
UL https://hdl.handle.net/10433/19960
LA en
NO Frontiers in Physiology, 13:898792.
NO Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain
NO CIBERER, Instituto de Salud Carlos III, Madrid, Spain
NO Departamento de Fisiología, Anatomía y Biología Celular
DS RIO
RD May 9, 2026