Format

Send to

Choose Destination
PLoS One. 2019 Feb 27;14(2):e0211568. doi: 10.1371/journal.pone.0211568. eCollection 2019.

Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver.

Author information

1
Genetics and Pharmacogenomics Department, MRL, Kenilworth, NJ, United States of America.
2
Biology-Discovery Department, MRL, Kenilworth, NJ, United States of America.
3
In Vivo Pharmacology Department, MRL, Kenilworth, NJ, United States of America.
4
In Vitro PharmacologyDepartment, MRL, NJ, United States of America.
5
Medicinal ChemistryDepartment, MRL, Kenilworth, NJ, United States of America.
6
PPDM Preclinical ADME Department, MRL, Kenilworth, NJ, United States of America.
7
SALAR Department, MRL, Kenilworth, NJ, United States of America.

Abstract

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.

Conflict of interest statement

All authors are or were employees of Merck & Co., Inc., Kenilworth, NJ, USA, and may own shares of company stock. Merck & Co., Inc., Kenilworth, NJ, USA, provisional patent applications for LA1, LA2, SA1 and SA2 and related AMPK activators were filed on 23 February 2012 (WO2012116145; Novel Cyclic Azabenzimidazole derivatives useful as anti-diabetic agents). All of the authors employed by Merck & Co., Inc., Kenilworth, NJ, USA, have a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center