Role of mitochondrial bioenergetics in skeletal muscle metabolism during exercise and pathology ; Papel de la bioenergética mitocondrial sobre el metabolismo del músculo esquelético durante el ejercicio y en patología
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Medientyp:
E-Book
Titel:
Role of mitochondrial bioenergetics in skeletal muscle metabolism during exercise and pathology ; Papel de la bioenergética mitocondrial sobre el metabolismo del músculo esquelético durante el ejercicio y en patología
Erschienen:
[Erscheinungsort nicht ermittelbar]: [Verlag nicht ermittelbar], 2022
Sprache:
Englisch
Identifikator:
Entstehung:
Hochschulschrift:
Dissertation, 2022
Anmerkungen:
Beschreibung:
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 11-04-2022 ; Metabolic pathologies and their complications are one of the main causes of death in western high-income countries. Mitochondria are key controllers of metabolism and the skeletal muscle (Skm) structure. However, whether Skm mitochondrial dysfunction is a cause or consequence of metabolic disorders is still controversial. In order to unveil the role of mitochondria in the onset and progression of these pathologies, in this thesis we have developed and characterized the first mouse model of conditional and Skm-specific inhibition of the mitochondrial H+-ATP synthase by the overexpression of its constitutively active inhibitor, ATPIF1/H49K. 6-month-old mice presenting the inhibition of the mitochondrial oxidative phosphorylation (OXPHOS) show a higher body weight compared to control littermates, due to deep alterations in glucose, lipid and amino acid metabolism in both muscle and white adipose tissue. Upon mitochondrial inhibition, Skm increases lactate production, reduces fatty acid β-oxidation, and relies on branched-chain amino acids catabolism as major source of acetyl-CoA for the de novo lipid synthesis. Moreover, acetyl-CoA accumulates in muscle and feedbacks the mitochondrial dysfunction by increasing the production of reactive oxygen species. As a result, mice with restrained OXPHOS become more prone to develop insulin resistance when fed a high-fat diet. Furthermore, Skm mitochondrial dysfunction alters motor behaviour, an effect that increases with ageing. 18-month-old mice presenting a chronic inhibition of the H+-ATP synthase show deep alterations in Skm organization, developing a myopathy characterized by the presence of tubular aggregates (TA), honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules that disorganize the sarcomere structure. The long-term OXPHOS inhibition reprograms soleus oxidative fibers to glycolytic ones, and increases ...