Assessing and unraveling sarcopeniarole of body weight in muscle wasting

Resumen

In this PhD Thesis we have tried to increase the knowledge about the mechanisms underlying sarcopenia progression. The excess of weight is considered as a powerful risk factor for the onset of muscle wasting and is studied through two different perspectives. In the first part of our work we have evaluated the effect of overweight in an elderly population, which has allowed us to identify the cellular alterations produced in an early stage of obesity and its relevance in aging. Overweight in the elders induces cellular bioenergetics depletion, altering cellular quality control mechanisms and thus, skeletal muscle maintenance. In the second part of this work, we have analyzed the skeletal muscle alterations in leptin deficient mice, as a model of severe obesity. Role and function of mitochondrial metabolism has been identified as essential for the regulation of cellular metabolism, especially in proteostasis balance. This study provides new mechanistic insights on the functional relevance of obesity in muscle quality and, supports the potential use of melatonin as a therapeutic supplement for obesity and its role on muscle-related preservation. Based on our results, melatonin appears to be a potential treatment for obesity-related disorders due to its ability to restore energy requirements by both mitochondrial remodeling and fuel utilization. Melatonin probably mitigates musculoskeletal alterations due the implication of circadian rhythms in fuel harvesting and energy homeostasis allowing the regulation of quality control mechanisms. In summary, these studies evidence that the excess of weight induces a metabolic reprogramming leading to a cellular metabolic modulation. However, what we face is not so much the increase in fat as such but the resulted metabolic imbalance, which leads to the alteration of the cellular mechanisms and the skeletal muscle wasting. Finally, by using C2C12 satellite cells, we have studied if the most relevant mechanism previously found could be involved in skeletal muscle impairment due to a lack of differentiation response of satellite cells. We found that senescence reprograms energy metabolism leading to altered autophagy and p66SHC responses. Similarly, our work demonstrates that autophagy and p66SHC are disrupted during the differentiation of senescent C2C12 cells leading to muscle wasting due to its implication in cell fate. The ability to reprogram these cellular pathways is an ambitious task and a future challenge to treat not only sarcopenia but also muscle atrophy.