Role of cyclic AMP-dependent effectors, PKA and EPAC, in the control of the Calcium-dependent proteolysis, caspase-mediated proteolysis and ubiquitin-proteasome system in diabetes muscle atrophy

• Grant number: 14/12202-0
• Support type: 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
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal researcher: Amanda Martins Baviera
• Grantee: Carlos Alberto Arcaro Filho
• Home 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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ARCARO, CARLOS ALBERTO; ASSIS, RENATA PIRES; OLIVEIRA, JULIANA ORIEL; ZANON, NEUSA MARIA; PAULA-GOMES, SILVIA; CARVALHO NAVEGANTES, LUIZ CARLOS; KETTELHUT, ISIS CARMO; BRUNETTI, IGUATEMY LOURENCO; BAVIERA, AMANDA MARTINS. Phosphodiesterase 4 inhibition restrains muscle proteolysis in diabetic rats by activating PKA and EPAC/Akt effectors and inhibiting FoxO factors. Life Sciences, v. 278, AUG 1 2021. Web of Science Citations: 0.

ARCARO, CARLOS ALBERTO; ASSIS, RENATA PIRES; ZANON, NEUSA MARIA; PAULA-GOMES, SILVIA; CARVALHO NAVEGANTES, LUIZ CARLOS; KETTELHUT, ISIS CARMO; BRUNETTI, IGUATEMY LOURENCO; BAVIERA, AMANDA MARTINS. Involvement of cAMP/EPAC/Akt signaling in the antiproteolytic effects of pentoxifylline on skeletal muscles of diabetic rats. Journal of Applied Physiology, v. 124, n. 3, p. 704-716, MAR 2018. Web of Science Citations: 1.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

FILHO, Carlos Alberto Arcaro. Inibidores de fosfodiesterases e o controle de processos proteolíticos na atrofia muscular induzida pelo diabetes mellitus. 2018. 154 f. Doctoral Thesis - Universidade Estadual Paulista "Júlio de Mesquita Filho" Faculdade de Ciências Farmacêuticas..