| Grant number: | 14/12202-0 |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| Effective date (Start): | September 01, 2014 |
| Effective date (End): | March 31, 2018 |
| Field of knowledge: | Biological Sciences - Biochemistry - Metabolism and Bioenergetics |
| Acordo de Cooperação: | Coordination of Improvement of Higher Education Personnel (CAPES) |
| Principal Investigator: | Amanda Martins Baviera |
| Grantee: | Carlos Alberto Arcaro Filho |
| Host Institution: | Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil |
| Associated scholarship(s): | 17/02348-5 - The role of PDE 4 in the autophagy control in skeletal muscles of rats, BE.EP.DR |
Abstract Increase in the intracellular levels of cyclic AMP (cAMP) is an essential event participating inthe inhibition of skeletal muscle protein degradation by catecholamines, after binding to beta 2-adrenoceptors. Two intracellular cAMP-dependent effectors seem to be involved in the antiproteolytic response of cAMP in the skeletal muscle: I) EPAC (Exchange protein directly activated by cAMP) that seems to inhibit the activity of ubiquitin-proteasome system through stimulation of AKT, a kinase responsible for inhibition of FoxO1/FoxO3a transcriptional factors, leading to a decrease in the atrogenes expression, II) PKA (cAMP-dependent kinase) that seems to inhibit the calcium-dependent proteolysis. Pharmacological inhibition of cAMP phosphodiesterases (PDE) leads to a decrease in the cAMP breakdown, culminating in increased cAMP levels e subsequent inhibition of muscle proteolysis. Knowing that PDE 4 accounts for the majority of PDE isoforms in skeletal muscles, PDE4 seems to be an interesting target to the development of selective strategies to promote an increase in the cAMP levels and inhibition of the muscle mass loss under conditions of atrophy. In addition, little is known about the role of cAMP in the control of the activity of the specific proteases participating in the muscle protein breakdown. Among these, it is crescent the evidences showing the involvement of the caspase-mediated proteolysis in the release of myofibrillar proteins from the sarcomere structure for the subsequent offer to ubiquitination and degradation for the proteasome, a role previously attributed only to the calpains. The project has as objective to investigate the role of PKA and EPAC effectors in the control of calcium-dependent proteolysis, caspase-mediated proteolysis and ubiquitin-proteasome system in the diabetes-induced atrophy, after an increase in the cAMP levels promoted by selective inhibition of PDE 4. (AU) | |
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