Calorie Restriction Rescues Mitochondrial Dysfunction in Adck2-Deficient Skeletal Muscle
Year: 2022
Type: article
Abstract: 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.
Source: Frontiers in Physiology
Institutions: Consejo Superior de Investigaciones Científicas, Instituto de Salud Carlos III, Centre for Biomedical Network Research on Rare Diseases, Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, Wolfspeed, Inc. (United States), Durham Public Schools, Institut de Recerca Sant Joan de Déu, Hospital Clínic de Barcelona, National Institutes of Health, National Institute on Aging
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,950
Funders: Association Française contre les Myopathies, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, European Commission, Ministerio de Educación, Cultura y Deporte, National Health Research Institutes, Junta de Andalucía, National Institutes of Health, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III
Awards: G1303036001, Diagnóstico molecular de los defectos de la fosforilación oxidativa mitocondrial: patogénesis de las deficiencias de CoQ10, G1660272867, G176523928, G2898265060, G308602422, Desarrollo de una plataforma para demostrar patogenicidad de variantes de significado incierto y nuevos genes causantes de enfermedad en pacientes con trastornos del metabolismo energético mitocondrial., G6951322904, G8267881827, G8679237682, G8776100923
OpenAlex ID: W4285389605