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Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis


AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor. Activation of AMPK leads to a number of metabolic benefits, including improved mitochondrial function in skeletal muscle and lowering of serum glucose levels in type-2 diabetes models. However, direct activation of AMPK leads to cardiac enlargement, and an alternative strategy that activates AMPK without affecting the heart is needed. Inhibition of phosphodiesterase 4 (PDE4), which is poorly expressed in the human heart, activates AMPK in other tissues. In a screen to identify novel PDE4 inhibitors, we discovered compound CBU91, which is 5-10 fold more potent than rolipram, the best characterized PDE4 inhibitor. CBU91, like rolipram, is able to activate AMPK and Sirt1 and increase mitochondrial function in myotubes. These findings suggest that activation of AMPK in myotubes is a general property of PDE4 inhibition and that PDE4 inhibition may activate AMPK in metabolically relevant tissues without affecting the heart.

Type Journal
ISBN 1932-6203 (Electronic) 1932-6203 (Linking)
Authors Park, S. J.; Ahmad, F.; Bahde, R. J.; Philp, A.; Kim, J.; Huang, T.; Kim, M. K.; Trenkle, W. C.; Chung, J. H.
Responsible Garvan Author Dr Andy Philp
Publisher Name PLoS One
Published Date 2021-06-17
Published Volume 16
Published Issue 6
Published Pages e0253269
Status Published in-print
DOI 10.1371/journal.pone.0253269
URL link to publisher's version