In a paper recently published in The EMBO Journal, researchers from the Autonomous University of Madrid (UAM) (Spain) have shown that the development of systemic metabolic diseases is dependent on the muscle activity of the mitochondrial enzyme ATP synthase, which is the ‘bottle neck’ of biological energy production.
The research
Using a mouse model that expresses the ATP synthase activity inhibitor in a regulated way, specifically in skeletal muscle, the researchers were able to demonstrate that mice that have a partially inhibited mitochondrial activity accumulate fat and are more likely to develop type 2 diabetes when fed a high fat diet.
“The mitochondrial energy crisis modifies the metabolism of the muscle cell, which begins to consume derived chain amino acids as a source of acetyl-CoA for lipid synthesis. This generates an alteration in lipid species and in the production of oxygen radicals, which ultimately contribute to the onset of insulin resistance,” the study authors pointed out.
Through a screening of drugs already approved by the FDA for clinical use, the researchers have identified the antioxidant Edaravone as a potent activator of the mitochondrial function, and therefore, as a possible treatment for this type of metabolic disease.
Obesity and muscles
Obesity is a chronic metabolic condition that affects all the organs and systems of the body, and even drives the onset of insulin resistance. In recent years, the central role played by the dysfunctions of the skeletal muscle – the largest insulin-sensitive organ in the body – in the development of metabolic pathologies has been revealed.
Muscle is an endocrine organ that secretes molecules and responds to hormones, which can contribute to the chronic inflammation associated with these diseases. Furthermore, muscle is the tissue that depends the most on the activity of mitochondria. These organelles are essential for muscle homeostasis, triggering a complex cellular response that controls the production of biological energy, thermogenesis, immunity, and the metabolism of amino acids and fatty acids, as well as signaling pathways mediated by calcium and reactive oxygen species.
For this reason, it is not surprising that mitochondrial abnormalities have been revealed in muscle biopsies of patients suffering from obesity and/or diabetes. Nevertheless, and in this context, it became a debate topic whether mitochondrial activity dysfunctions are the cause or a consequence of insulin resistance.
The findings
“Our work demonstrates, for the first time, that the metabolic alteration that occurs in skeletal muscle mitochondria is the cause of the obese phenotype in our mice, which contributed to the development of diabetes,” according to Cristina Sánchez González, first author of the study.
These findings are of great importance in the study of metabolic diseases and their possible treatment. “The early detection of a mitochondrial alteration at the muscular level could be an early marker of the disease, providing the possibility to be treated with Edaravone when it is still reversible,” the authors concluded.
The study was led by Laura Formentini, Ramón y Cajal researcher at the UAM, who leads an emerging group integrated at Professor J.M. Cuezva’s lab at the Severo Ochoa Molecular Biology Center, UAM-CSIC mixed center. The study also included researchers from the Rare Diseases Biomedical Research Center (CIBERER-ISCIII), the Hospital 12 de Octubre Research Institute (i + 12-UAM) and the Instituto Madrileño de Estudios Avanzados (IMDEA).
Link: https://www.sochob.cl/web1/la-obesidad-tambien-depende-de-la-actividad-de-las-mitocondrias-del-musculo/
Date: July 11th, 2020
Source: https://noticiasdelaciencia.com
Reference: Sánchez González C, Nuevo-Tapioles C, Herrero JC, et al. Dysfunctional oxidative phosphorylation shunts branched?chain amino acid catabolism onto lipogenesis in skeletal muscle. EMBO J. 2020 Jun 3;e103812.
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