Open AccessPotent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis
Author(s) -
Sung-Jun Park,
Faiyaz Ahmad,
Robert J. Bahde,
Andrew Philp,
JeongHan Kim,
Tianjiao Huang,
Myung K. Kim,
William C. Trenkle,
Jay H. Chung
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0253269
Subject(s) - ampk , rolipram , amp activated protein kinase , mitochondrial biogenesis , protein kinase a , phosphodiesterase , microbiology and biotechnology , chemistry , mitochondrion , endocrinology , medicine , biology , biochemistry , phosphorylation , enzyme
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.