In our previous thematic project, we have shown that the sympathetic nervous system through the beta 2-adrenoceptors activation inhibits the activity of ubiquitin-proteasome system (UPS), the major proteolytic system involved in muscle wasting. This effect is due to the suppression of "atrophy program" (atrophy-related genes or atrogenes) and involves the cAMP signaling pathway. However, the mechanisms that underlie such function of cAMP and its downstream effectors in the control of muscle mass remain unknown. Therefore, the main goals of the present project are: 1-To investigate the involvement of histone deacetylases and the CREB co-activators (p300/CBP) in the acetylation of Foxo as a mechanism of inhibition of atrogenes induced by beta 2-agonists; 2-To verify the role of PKA/CREB as an adaptive mechanism response to attenuate muscle loss in chronically denervated muscles; 3-To explore the possible interaction between cAMP and myostatin signaling pathway in the control of muscle mass; 4-To investigate the antiproteolitic mechanisms and signaling pathways involved in the anabolic action of additional cAMP-inducing agents (CGRP and Urocortins) and 5-To establish whether the adrenergic mechanisms regulating protein turnover in the brown adipose tissue are similar to those in the skeletal muscle. To that end, we shall use molecular and biochemical approaches to measure proteolytic activities and the expression of genes and proteins in tissues and cells. Furthermore, in vivo techniques of molecular biology, such as gene transfer by electroporation and the analysis of transcriptional factor activity by imaging system will be implanted in our lab. Therefore, Foxo acetylation status will be able to be correlated with the in vivo transcriptional activity of Foxo and the expression level of atrogenes in muscles from rodents submitted to different atrophic models and treated with beta 2-agonists and other compounds. To further investigate the signaling pathways involved in the anticatabolic action of cAMP, skeletal muscles will be transfected with dominant negative forms of PKA, CREB, ERK2 or Akt. These results may contribute to the development of therapeutic strategies to combat muscle atrophy. (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
KHAN, MUZAMIL MAJID;
SILVEIRA, WILLIAN A.;
KETTELHUT, ISIS C.;
NAVEGANTES, LUIZ C. C.;
Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease.
Proceedings of the National Academy of Sciences of the United States of America,
JAN 19 2016.
Web of Science Citations: 32.