MicroRNA-34a causes ceramide accumulation and effects insulin signaling pathway by targeting ceramide kinase (CERK) in aging skeletal muscle
| Autor: | Himani Kukreti, Kottaiswamy Amuthavalli |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male Ceramide Aging Myostatin Ceramides Biochemistry Myoblasts 03 medical and health sciences chemistry.chemical_compound Mice Young Adult 0302 clinical medicine Ceramide kinase medicine Myocyte Animals Humans Insulin Computer Simulation Muscle Skeletal Molecular Biology 3' Untranslated Regions biology Skeletal muscle Cell Biology musculoskeletal system Cell biology Up-Regulation Mice Inbred C57BL Insulin receptor MicroRNAs Phosphotransferases (Alcohol Group Acceptor) 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis biology.protein Insulin Resistance C2C12 GLUT4 Signal Transduction |
| Zdroj: | Journal of cellular biochemistryREFERENCES. 121(5-6) |
| ISSN: | 1097-4644 |
| Popis: | Aging skeletal muscle shows perturbations in metabolic functions. MicroRNAs have been shown to play a critical role in aging and metabolic functions of skeletal muscle. MicroRNA-34a (miR-34a) is implicated in the brain and cardiac aging, however, its role in aging muscle is unclear. We analyzed levels of miR-34a, ceramide kinase (CERK) and other insulin signaling molecules in skeletal muscle from old mice. In addition to in vivo model, levels of these molecules were also analyzed in myoblast derived from insulin resistant (IR) humans and C2C12 myoblasts overexpressing mir-34a. Our results show that miR-34a is elevated in the muscles of 2-year-old mice and in the myoblasts of IR humans. Overexpression of miR-34a in C2C12 myoblasts leads to alterations in the insulin signaling pathway, which were rescued by its antagonism. Our analyses revealed that miR-34a targets CERK resulting in ceramide accumulation, activation of PP2A and the pJNK pathway in muscle and C2C12 myoblasts. Also, myostatin (Mstn) levels were increased in 2-year-old mouse muscle and Mstn treatment upregulated miR-34a in C2C12 myoblasts. In addition, miR-34a expression and ceramide levels did not increase during aging in Mstn-/- mice muscle. In summary, we, therefore, propose that Mstn levels increase in aging muscle and upregulate miR-34a, which inhibits CERK resulting in increased ceramide levels. This ceramide accumulation activates PP2A and pJNK causing hypophosphorylation of AKT and hyperphosphorylation of IRS1 (Ser307), respectively, impairing insulin signaling pathway and eventually inhibiting the sarcolemma localization of GLUT4. These changes would result in reduced glucose uptake and insulin resistance. This study is the first to explain the phenomenon of ceramide accrual and impairment of insulin signaling pathway in aging muscle through a miR-34a based mechanism. In conclusion, our results suggest that Mstn and miR-34a antagonism can help ameliorate ceramide accumulation and loss of insulin sensitivity in aging skeletal muscle. |
| Databáze: | OpenAIRE |
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