2. Academic Validation
  3. Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis

Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis

  • PLoS One. 2021 Jun 17;16(6):e0253269. doi: 10.1371/journal.pone.0253269.
Sung-Jun Park 1,  Faiyaz Ahmad 2,  Robert J Bahde 3,  Andrew Philp 4,  Jeonghan Kim 1,  Tianjiao Huang 1,  Myung K Kim 1,  William C Trenkle 3,  Jay H Chung 1
Affiliations

Affiliations

  • 1 Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
  • 2 Department of Pediatric Medicine, Division of Endocrinology, Sidra Medical and Research Center, Doha, Qatar.
  • 3 Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
  • 4 Mitochondrial Metabolism and Ageing Laboratory, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, Australia.
PMID: 34138962 DOI: 10.1371/journal.pone.0253269
Abstract

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.

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