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This Article Full Text Full Text (PDF) All Versions of this Article: 292/3/E702    most recent 00147.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Baviera, A. M. Articles by Kettelhut, I. d. C. Search for Related Content PubMed PubMed Citation Articles by Baviera, A. M. Articles by Kettelhut, I. d. C.

Pentoxifylline inhibits Ca²⁺-dependent and ATP proteasome-dependent proteolysis in skeletal muscle from acutely diabetic rats

Departments of Biochemistry and Immunology and Physiology, School of Medicine, University of São Paulo, Ribeirão Preto São Paulo, Brazil

Submitted 28 March 2006 ; accepted in final form 25 October 2006

Previous studies from this laboratory have shown that catecholamines exert an inhibitory effect on muscle protein degradation through a pathway involving the cAMP cascade. The present work investigated the systemic effect of pentoxifylline (PTX; cAMP-phosphodiesterase inhibitor) treatment on the rate of overall proteolysis, the activity of proteolytic systems, and the process of protein synthesis in extensor digitorum longus muscles from normal and acutely diabetic rats. The direct in vitro effect of this drug on the rates of muscle protein degradation was also investigated. Muscles from diabetic rats treated with PTX showed an increase (22%) in the cAMP content and reduction in total rates of protein breakdown and in activity of Ca²⁺-dependent (47%) and ATP proteasome-dependent (23%) proteolytic pathways. The high content of m-calpain observed in muscles from diabetic rats was abolished by PTX treatment. The addition of PTX (10^–3 M) to the incubation medium increased the cAMP content in muscles from normal (22%) and diabetic (51%) rats and induced a reduction in the rates of overall proteolysis that was accompanied by decreased activity of the Ca²⁺-dependent and ATP proteasome-dependent proteolytic systems, in both groups. The in vitro addition of H-89, an inhibitor of protein kinase A (PKA), completely blocked the effect of PTX on the reduction of proteolysis in muscles from normal and diabetic rats. The present data suggest that PTX exerts a direct inhibitory effect on protein degradative systems in muscles from acutely diabetic rats, probably involving the participation of cAMP intracellular pathways and activation of PKA, independently of tumor necrosis factor- inhibition.

adenosine 3',5'-cyclic monophosphate-phosphodiesterase inhibitors; muscle atrophy; streptozotocin-diabetic rats; adenosine 3',5'-cyclic monophosphate-dependent pathway; xanthine derivatives