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EPAC/AKT/FoxO signaling and the control of the caspase-mediated proteolytic process and of the ubiquitin-proteasome system in diabetes muscle atrophy


It has been demonstrated that the inhibitory effect of catecholamines in the protein breakdown in skeletal muscles occurs, at least in part, through stimulation of beta2-adrenoceptors and increase in the intracellular levels of cyclic AMP (cAMP), involving the participation of two signaling cascades: i) an EPAC (Exchange protein directly activated by cAMP) dependent pathway, which leads to stimulation of AKT, inhibition of FoxO1/FoxO3a transcriptional factors and suppression of ubiquitin-proteasome system (UPS), and ii) a PKA-dependent pathway, which could decrease calcium-dependent proteolytic pathway. There is no study about the role of the cAMP signaling in the control of the caspase-mediated proteolysis, an intracellular process involved in both installation and maintenance of muscle atrophy; this process is essential for the dissociation of myofibrilar protein from sarcomere structure and subsequent offer of substrates for ubiquitination and degradation by the proteasome. Therefore, the association of i) a cAMP-dependent signaling that stimulates EPAC/AKT and inhibits FoxO1/FoxO3a, and ii) the participation of FoxO factors in the control of the caspase-mediated proteolysis, seems to be a promissory area of investigation. The understanding of the intracellular signals involved in the control of the caspase-mediated proteolysis will be useful to indicate important targets to the development of strategies in the control and/or reduction of muscle atrophy conditions. (AU)

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(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; 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.

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