Involvement of cAMP/EPAC/Akt signaling in the antiproteolytic effects of pentoxifylline on skeletal muscles of diabetic rats

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dc.contributor.authorArcaro, Carlos Alberto [UNESP]
dc.contributor.authorAssis, Renata Pires [UNESP]
dc.contributor.authorZanon, Neusa Maria
dc.contributor.authorPaula-Gomes, Silvia
dc.contributor.authorCarvalho Navegantes, Luiz Carlos
dc.contributor.authorKettelhut, Isis Carmo
dc.contributor.authorBrunetti, Iguatemy Lourenco [UNESP]
dc.contributor.authorBaviera, Amanda Martins [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.date.accessioned2018-11-26T17:48:54Z
dc.date.available2018-11-26T17:48:54Z
dc.date.issued2018-03-01
dc.description.abstractAdvances in the knowledge of the mechanisms controlling protein breakdown in skeletal muscles have allowed the exploration of new options for treating muscle-wasting conditions. Pentoxifylline (PTX), a nonselective phosphodiesterase (PDE) inhibitor, attenuates the loss of muscle mass during catabolic conditions, mainly via inhibiting protein breakdown. The aim of this study was to explore the mechanisms by which PTX inhibits proteolysis in the soleus and extensor digitorum longus (EDL) muscles of streptozotocin-induced diabetic rats. The levels of atrogin-1 and muscle RING finger-1 were decreased, as were the activities of caspase-3 (EDL) and calpains (soleus and EDL), in diabetic rats treated with PTX, which at least partly explains the drop in the ubiquitin conjugate (EDL) levels and in proteasome activity (soleus and EDL). Treatment with PTX decreased PDE activity and increased cAMP content in muscles of diabetic rats; moreover, it also increased both the protein levels of exchange protein directly activated by cAMP (EPAC, a cAMP effector) and the phosphorylation of Akt. The loss of muscle mass was practically prevented in diabetic rats treated with PTX. These findings advance our understanding of the mechanisms underlying the antiproteolytic effects of PTX and suggest the use of PDE inhibitors as a strategy to activate cAMP signaling, which is emerging as a promising target for treating muscle mass loss during atrophic conditions. NEW & NOTEWORTHY cAMP signaling has been explored as a strategy to attenuate skeletal muscle atrophies. Therefore, in addition to beta(2)AR agonists, phosphodiesterase inhibitors such as pentoxifylline (PTX) can be an interesting option. This study advances the understanding of the mechanisms related to the antiproteolytic effects of PTX on skeletal muscles of diabetic rats, which involve the activation of both exchange protein directly activated by cAMP and Akt effectors, inhibiting the expression of atrogenes and calpain/caspase-3-proteolytic machinery.en
dc.description.affiliationUniv Sao Paulo, Sao Paulo State Univ, Sch Pharmaceut Sci, Dept Clin Anal, Rod Araraquara Jau Km 01 S-N, BR-14800903 Araraquara, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Ribeirao Preto Med Sch, Dept Physiol, Ribeirao Preto, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem Immunol, Ribeirao Preto, SP, Brazil
dc.description.affiliationUnespUniv Sao Paulo, Sao Paulo State Univ, Sch Pharmaceut Sci, Dept Clin Anal, Rod Araraquara Jau Km 01 S-N, BR-14800903 Araraquara, SP, Brazil
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipScientific Support and Development Program of School of Pharmaceutical Sciences of UNESP (PADC/FCFAr/UNESP)
dc.description.sponsorshipIdFAPESP: 2013/18861-2
dc.description.sponsorshipIdCNPq: 479817/2013-8
dc.description.sponsorshipIdScientific Support and Development Program of School of Pharmaceutical Sciences of UNESP (PADC/FCFAr/UNESP): 26/2013
dc.description.sponsorshipIdFAPESP: 2014/12202-0
dc.format.extent704-716
dc.identifierhttp://dx.doi.org/10.1152/japplphysiol.00499.2017
dc.identifier.citationJournal Of Applied Physiology. Bethesda: Amer Physiological Soc, v. 124, n. 3, p. 704-716, 2018.
dc.identifier.doi10.1152/japplphysiol.00499.2017
dc.identifier.issn8750-7587
dc.identifier.urihttp://hdl.handle.net/11449/164047
dc.identifier.wosWOS:000428784900018
dc.language.isoeng
dc.publisherAmer Physiological Soc
dc.relation.ispartofJournal Of Applied Physiology
dc.relation.ispartofsjr1,471
dc.rights.accessRightsAcesso restrito
dc.sourceWeb of Science
dc.subjectAkt
dc.subjectcAMP/EPAC signaling
dc.subjectpentoxifylline
dc.subjectskeletal muscle proteolysis
dc.subjectstreptozotocin-diabetic rats
dc.titleInvolvement of cAMP/EPAC/Akt signaling in the antiproteolytic effects of pentoxifylline on skeletal muscles of diabetic ratsen
dc.typeArtigo
dcterms.rightsHolderAmer Physiological Soc
unesp.author.lattes3736475025187750[8]
unesp.author.orcid0000-0003-0987-5295[8]

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