期刊
LIFE SCIENCES
卷 278, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2021.119563
关键词
Rolipram; Diabetes mellitus; Skeletal muscle; Proteolysis; Ubiquitin-proteasome system
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/18861-2]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [479817/2013-8]
- Programa de Apoio ao Desenvolvimento Cientifico da Faculdade de Ciencias Farmaceuticas da Unesp (PADC/FCFAr/UNESP) [26/2013]
- FAPESP [2014/12202-0]
The study showed that rolipram, a selective PDE4 inhibitor, can inhibit protein breakdown in skeletal muscles of diabetic rats by activating cAMP downstream effectors, ultimately leading to the preservation of muscle mass.
Aim: There is growing evidence about the ability of cyclic adenosine monophosphate (cAMP) signaling and nonselective phosphodiesterase (PDE) inhibitors on mitigate muscle atrophy. PDE4 accounts for the major cAMP hydrolyzing activity in skeletal muscles, therefore advances are necessary about the consequences of treatment with PDE4 inhibitors on protein breakdown in atrophied muscles. We postulated that rolipram (selective PDE4 inhibitor) may activate cAMP downstream effectors, inhibiting proteolytic systems in skeletal muscles of diabetic rats. Main methods: Streptozotocin-induced diabetic rats were treated with 2 mg/kg rolipram for 3 days. Changes in the levels of components belonging to the proteolytic machineries in soleus and extensor digitorum longus (EDL) muscles were investigated, as well as cAMP effectors. Key findings: Treatment of diabetic rats with rolipram decreased the levels of atrogin-1 and MuRF-1 in soleus and EDL, and reduced the activities of calpains and caspase-3; these findings partially explains the low ubiquitin conjugates levels and the decreased proteasome activity. The inhibition of muscle proteolysis may be occurring due to phosphorylation and inhibition of forkhead box O (FoxO) factors, probably as a consequence of the increased cAMP levels, followed by the activation of PKA and Akt effectors. Akt activation may be associated with the increased levels of exchange protein directly activated by cAMP (EPAC). As a result, rolipram treatment spared muscle mass in diabetic rats. Significance: The antiproteolytic responses associated with PDE4 inhibition may be helpful to motivate future investigations about the repositioning of PDE4 inhibitors for the treatment of muscle wasting conditions.
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