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miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia

Metformin is the most used biguanide drug for the treatment of type 2 diabetes mellitus. Despite being mostly known for its hepatic anti-gluconeogenic effect, it is also known to modulate microRNAs (miRNAs, miRs) associated with metabolic diseases. The latter mechanism could be relevant for better u...

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Autores principales: Machado, Ivo F., Teodoro, João S., Castela, Ana C., Palmeira, Carlos M., Rolo, Anabela P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827403/
https://www.ncbi.nlm.nih.gov/pubmed/33430391
http://dx.doi.org/10.3390/ijms22020541
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author Machado, Ivo F.
Teodoro, João S.
Castela, Ana C.
Palmeira, Carlos M.
Rolo, Anabela P.
author_facet Machado, Ivo F.
Teodoro, João S.
Castela, Ana C.
Palmeira, Carlos M.
Rolo, Anabela P.
author_sort Machado, Ivo F.
collection PubMed
description Metformin is the most used biguanide drug for the treatment of type 2 diabetes mellitus. Despite being mostly known for its hepatic anti-gluconeogenic effect, it is also known to modulate microRNAs (miRNAs, miRs) associated with metabolic diseases. The latter mechanism could be relevant for better understanding metformin’s mechanisms underlying its biological effects. In the current work, we found that metformin increases miR-378a-3p expression (p < 0.002) in C2C12 myoblasts previously exposed to hyperglycemic conditions. While the inhibition of miR-378a-3p was shown to impair metformin’s effect in ATP production, PEPCK activity and the expression of Tfam. Finally, mitophagy, an autophagic process responsible for the selective degradation of mitochondria, was found to be induced by miR-378a-3p (p < 0.04). miR-378a-3p stimulated mitophagy through a process independent of sestrin-2 (SESN2), a stress-responsible protein that has been recently demonstrated to positively modulate mitophagy. Our findings provide novel insights into an alternative mechanism of action of metformin involving miR-378a-3, which can be used in the future for the development of improved therapeutic strategies against metabolic diseases.
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spelling pubmed-78274032021-01-25 miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia Machado, Ivo F. Teodoro, João S. Castela, Ana C. Palmeira, Carlos M. Rolo, Anabela P. Int J Mol Sci Article Metformin is the most used biguanide drug for the treatment of type 2 diabetes mellitus. Despite being mostly known for its hepatic anti-gluconeogenic effect, it is also known to modulate microRNAs (miRNAs, miRs) associated with metabolic diseases. The latter mechanism could be relevant for better understanding metformin’s mechanisms underlying its biological effects. In the current work, we found that metformin increases miR-378a-3p expression (p < 0.002) in C2C12 myoblasts previously exposed to hyperglycemic conditions. While the inhibition of miR-378a-3p was shown to impair metformin’s effect in ATP production, PEPCK activity and the expression of Tfam. Finally, mitophagy, an autophagic process responsible for the selective degradation of mitochondria, was found to be induced by miR-378a-3p (p < 0.04). miR-378a-3p stimulated mitophagy through a process independent of sestrin-2 (SESN2), a stress-responsible protein that has been recently demonstrated to positively modulate mitophagy. Our findings provide novel insights into an alternative mechanism of action of metformin involving miR-378a-3, which can be used in the future for the development of improved therapeutic strategies against metabolic diseases. MDPI 2021-01-07 /pmc/articles/PMC7827403/ /pubmed/33430391 http://dx.doi.org/10.3390/ijms22020541 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Machado, Ivo F.
Teodoro, João S.
Castela, Ana C.
Palmeira, Carlos M.
Rolo, Anabela P.
miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia
title miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia
title_full miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia
title_fullStr miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia
title_full_unstemmed miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia
title_short miR-378a-3p Participates in Metformin’s Mechanism of Action on C2C12 Cells under Hyperglycemia
title_sort mir-378a-3p participates in metformin’s mechanism of action on c2c12 cells under hyperglycemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827403/
https://www.ncbi.nlm.nih.gov/pubmed/33430391
http://dx.doi.org/10.3390/ijms22020541
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