Role of mitochondrial bioenergetics in skeletal muscle metabolism during exercise and pathology
Title (trans.)
Papel de la bioenergética mitocondrial sobre el metabolismo del músculo esquelético durante el ejercicio y en patologíaAuthor
Sánchez González, CristinaAdvisor
Formentini, LauraEntity
UAM. Departamento de Biología Molecular; Centro de Biología Molecular Severo Ochoa (CBM)Date
2022-02-11Funded by
This work has been supported by a predoctoral fellowship from the Spanish Ministerio de Economía y Competitividad (BES-2017-079909). The project was funded by the Spanish Ministerio de Economía y Competitividad (Grants SAF2016-76028- R and PID2019- 104241RB-I00)Subjects
Mitocondrias; Enfermedades metabólicas; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 11-04-2022Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
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 mitochondrial fission and mitophagy, presumably to recycle defective
mitochondria. TA appeared as the result of SR tubulation aimed at increasing mitochondria/SR
contact sites to buffer calcium overloads due to prolonged OXPHOS dysfunction.
Hence, enhancing OXPHOS activity appears as a promising strategy for therapeutic
intervention in metabolic and muscle disorders. With this aim, we screened 702 drugs and identified
edaravone as a new mitochondrial antioxidant and enhancer. Remarkably, in vivo edaravone
treatment restores a healthy phenotype both in 6-month and 18-month old mice. Altogether,
these results suggest that Skm mitochondrial alterations contribute to the setting of metabolic and
muscular disorders, proposing edaravone as a potential treatment for these pathologies
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