biostudies-literatureMachado IFFundação para a Ciência e a TecnologiaEuropean Regional Development FundE541https://www.ebi.ac.uk/biostudies/studies/S-EPMC7827403biostudies-literatureUnknown22(2)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-378International journal of molecular sciencesmiR-378a-3p Participates in Metformin's Mechanism of Action on C2C12 Cells under Hyperglycemia.PMC7827403CEECIND/4400/2017POCI-01-0145-FEDER-016770UID/NEU/04539/2013HEALTHYAGING 2020 CENTRO-01- 0145-FEDER-000012CENTRO-01-0145-FEDER-000012- HealthyAging2020Machado IFRolo APPalmeira CMTeodoro JSCastela ACfalsemiR-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 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-3782021-01-01T00:00:00Z2021 Jan2025-04-04T10:55:30.679Z2025-04-04T10:55:30.679ZS-EPMC78274033343039110.3390/ijms22020541