Functional and molecular mechanisms involved in the actions of bile acid TUDCA in skeletal musculature in the face of aging

Abstract

According to the World Health Organization, it is expected that by 2050 the world population over 60 years of age will double, reaching almost 2 billion. Aging is related to a greater propensity for the emergence of cardiovascular diseases, cancer, neurodegenerative diseases, type II diabetes mellitus, and changes in body composition and morphology, such as an increase in adipose tissue and a decrease in muscle mass. In elderly individuals, loss of skeletal muscle mass associated with loss of tissue function characterizes sarcopenia. This condition is associate with several factors such as decreased nutrient absorption, chronic inflammation in various tissues, decreased signaling of hormones such as insulin, which reflect in the upregulation of proteolysis pathways and downregulation of protein synthesis in muscle. Sarcopenia reduces mobility and increases the risk of falling and the development or aggravation of metabolic diseases such as diabetes and obesity. Therefore, it is necessary to develop new studies capable of elucidating the mechanisms of sarcopenia as strategies capable of alleviating this condition. Bile acids are effective in the treatment of several metabolic diseases in many experimental models, among them the tauroursodeoxycholic bile acid (TUDCA) stands out for having a broad systemic action, and low toxicity in humans. It is known that TUDCA can reduce reticulum stress in several cell types, attenuate type I diabetes mellitus damage, in addition to increasing insulin sensitivity in peripheral tissues. In skeletal muscle tissue, studies also show that TUDCA can attenuate muscle atrophy in animals undergoing treatment with dexamethasone, a compensating for the harmful effects of the drug on this tissue by mechanisms that have not been elucidated. Preliminary results from our study group show that 18-month-old senile mice have a significant loss of muscle mass in the gastrocnemius, soleus, tibialis anterior, and EDL muscles, as well as a drastic reduction in their strength when compared to control animals. All these changes were attenuated after treatment with TUDCA, showing a beneficial potential of this bile acid in attenuating sarcopenia in this model. Although the beneficial actions of TUDCA involved in the maintenance of muscle tissue have already been observed, little is known about the molecular mechanisms by which this bile acid acts, especially in models where muscle loss is related to aging. Thus, considering the functional and molecular changes related to loss of muscle mass and function, and our preliminary results, this project aims to investigate the role of bile acid TUDCA on the attenuation of sarcopenia in senile mice treated with this bile acid, as well as to elucidate its mechanisms of action in skeletal muscle cells C2C12. (AU)