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 AMP...

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Autores principales:	Sung-Jun Park, Faiyaz Ahmad, Robert J Bahde, Andrew Philp, Jeonghan Kim, Tianjiao Huang, Myung K Kim, William C Trenkle, Jay H Chung
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/feec3c253475457eb9c0174e3e2d56d8
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id	oai:doaj.org-article:feec3c253475457eb9c0174e3e2d56d8
record_format	dspace
spelling	oai:doaj.org-article:feec3c253475457eb9c0174e3e2d56d82021-12-02T20:10:25ZPotent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.1932-620310.1371/journal.pone.0253269https://doaj.org/article/feec3c253475457eb9c0174e3e2d56d82021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253269https://doaj.org/toc/1932-6203AMP-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.Sung-Jun ParkFaiyaz AhmadRobert J BahdeAndrew PhilpJeonghan KimTianjiao HuangMyung K KimWilliam C TrenkleJay H ChungPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0253269 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sung-Jun Park Faiyaz Ahmad Robert J Bahde Andrew Philp Jeonghan Kim Tianjiao Huang Myung K Kim William C Trenkle Jay H Chung Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.
description	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.
format	article
author	Sung-Jun Park Faiyaz Ahmad Robert J Bahde Andrew Philp Jeonghan Kim Tianjiao Huang Myung K Kim William C Trenkle Jay H Chung
author_facet	Sung-Jun Park Faiyaz Ahmad Robert J Bahde Andrew Philp Jeonghan Kim Tianjiao Huang Myung K Kim William C Trenkle Jay H Chung
author_sort	Sung-Jun Park
title	Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.
title_short	Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.
title_full	Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.
title_fullStr	Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.
title_full_unstemmed	Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.
title_sort	potent pde4 inhibitor activates ampk and sirt1 to induce mitochondrial biogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/feec3c253475457eb9c0174e3e2d56d8
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_version_	1718375040895942656

Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis.

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