Department of Clinical Analysis, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, University of São Paulo , São Paulo , Brazil.
Department of Physiology, University of São Paulo, Ribeirão Preto Medical School , Ribeirão Preto, São Paulo , Brazil.
J Appl Physiol (1985). 2018 Mar 1;124(3):704-716. doi: 10.1152/japplphysiol.00499.2017. Epub 2017 Dec 14.
Advances 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 βAR 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.
在控制骨骼肌蛋白分解机制方面的知识进展，使人们能够探索治疗肌肉减少症的新选择。己酮可可碱（PTX）是一种非选择性磷酸二酯酶（PDE）抑制剂，可通过抑制蛋白分解来减轻分解代谢状态下的肌肉质量损失。本研究旨在探讨 PTX 抑制链脲佐菌素诱导的糖尿病大鼠比目鱼肌和趾长伸肌（EDL）蛋白水解的机制。在接受 PTX 治疗的糖尿病大鼠中，肌肉萎缩因子-1 和肌肉 RING 指蛋白-1 的水平降低，caspase-3（EDL）和钙蛋白酶（比目鱼肌和 EDL）的活性降低，这至少部分解释了泛素缀合物（EDL）水平和蛋白酶体活性（比目鱼肌和 EDL）的下降。PTX 治疗降低了糖尿病大鼠肌肉中的 PDE 活性和 cAMP 含量；此外，它还增加了 cAMP 效应物交换蛋白直接激活蛋白（EPAC）的蛋白水平和 Akt 的磷酸化。在接受 PTX 治疗的糖尿病大鼠中，肌肉质量的损失几乎得到了预防。这些发现增进了我们对 PTX 抗蛋白水解作用机制的理解，并表明使用 PDE 抑制剂作为激活 cAMP 信号的策略，这正在成为治疗萎缩状态下肌肉质量损失的有前途的靶点。新观点和重要发现 cAMP 信号已被探索作为减轻骨骼肌萎缩的策略。因此，除了βAR 激动剂外，磷酸二酯酶抑制剂（如己酮可可碱）也可能是一个有趣的选择。本研究增进了我们对 PTX 对糖尿病大鼠骨骼肌抗蛋白水解作用机制的理解，该机制涉及 cAMP 直接激活的交换蛋白和 Akt 效应物的激活，抑制了萎缩基因和钙蛋白酶/caspase-3 蛋白水解机制的表达。
