Role of rev-erb-alpha in aging-associated endoplasmic reticulum stress

Abstract

Aging is associated with a progressive reduction in muscle strength, muscle mass, and physical performance (sarcopenia). Estimates indicate that every 10 years the loss of muscle mass is 8% after age 40 and increases to 15% per decade after age 70. When it comes to muscle strength, the numbers are even more aggressive. An important organelle responsible for muscle maintenance through protein synthesis and degradation is the endoplasmic reticulum (ER). When stressed, the ER triggers an unfolded protein response (UPR) to return protein homeostasis within the ER. Elderly individuals present a worsening in the UPR and, consequently, high ER stress that can lead to cellular apoptosis. Recently, sarcopenia has been classified as a disease and this fact has brought the possibility of establishing guidelines for its diagnosis and treatment. Therefore, the rev-erb-alpha protein is a promising molecular target for the prevention and treatment of this disease, since, in addition to having an important role in the regulation of autophagy, mitochondrial content, oxidative function and maintenance of skeletal muscle mass, it seems to regulate also UPR markers and relieve ER stress. Therefore, the aim of the present project is to verify 1) the effect of aging on rev-erb-alpha, ER stress and apoptosis, 2) the effect of conditional deletion (skeletal muscle) of the Nr1d1 gene on ER stress markers and apoptosis, 3) effect of pharmacological activation of Nr1d1 on ER stress and apoptosis, 4) Effect of chronic physical exercise on rev-erb-alpha, ER stress and apoptosis during aging, and 5) the role of rev-erb-alpha in ER adaptations in response to stress generated by physical exercise.