Down‐regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes

Abstract

Fetal cardiomyocytes shift from glycolysis to oxidative phosphorylation around the time of birth. Myeloid ecotropic viral integration site 1 (MEIS1) is a transcription factor that promotes glycolysis in hematopoietic stem cells. We reasoned that MEIS1 could have a similar role in the developing heart. We hypothesized that suppression of MEIS1 expression in fetal sheep cardiomyocytes leads to a metabolic switch as found at birth. Expression of MEIS1 was assayed in left ventricular cardiac tissue and primary cultures of cardiomyocytes from fetal (100‐ and 135‐d gestation, term = 145 d), neonatal, and adult sheep. Cultured cells were treated with short interfering RNA (siRNA) to suppress MEIS1. Oxygen consumption rate was assessed with the Seahorse metabolic flux analyzer, and mitochondrial activity was assessed by staining cells with MitoTracker Orange. Cardiomyocyte respiratory capacity increased with advancing age concurrently with decreased expression of MEIS1. MEIS1 suppression with siRNA increased maximal oxygen consumption in fetal cells but not in postnatal cells. Mitochondrial activity was increased and expression of glycolytic genes decreased when MEIS1 expression was suppressed. Thus, we conclude that MEIS1 is a key regulator of cardiomyocyte metabolism and that the normal down‐regulation of MEIS1 with age underlies a gradual switch to oxidative metabolism.—Lindgren, I. M., Drake, R. R., Chattergoon, N. N., Thornburg, K. L. Down‐regulation of MEIS1 promotes the maturation of oxidative phosphorylation in perinatal cardiomyocytes. FASEB J. 33, 7417–7426 (2019). http://www.fasebj.org

Temporal Analyses of Postnatal Liver Development and Maturation by Single Cell Transcriptomics

“…In mammals, many cell types including hepatocytes use glycolysis as the main source of energy in the fetus due to low oxygen concentration and the immaturity of mitochondria. In the newborn, the metabolic energy source shifts as the activity of mitochondrial oxidative phosphorylation increases rapidly with air breathing (Böhme et al, 1983;Lindgren et al, 2019). As expected, we observed dramatic decrease in the expression of hypoxia-related pathway from D1 to D56 (Figure 3F).…”

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

“…Additional regulators can affect both the cell cycle and the metabolic switch in cardiomyocytes. MEIS1, a transcription factor that stimulates cell cycle activity in cardiomyocytes [216], also supports a less mature metabolic phenotype in cardiomyocytes by promoting glycolysis, while MEIS1 siRNA in fetal sheep cardiomyocytes triggers a metabolic switch from glycolysis to oxidative phosphorylation [217]. Deletion of endonuclease G, a mitochondrial enzyme that promotes apoptosis during oxidative stress, increases ROS levels, reduces proliferative capacity of cardiomyocytes in mice, and increases cardiomyocyte size, with cell cycle arrest in the G1 phase [218].…”

Overexpression of microRNAs miR-25-3p, miR-185-5p and miR-132-3p in Late Onset Fetal Growth Restriction, Validation of Results and Study of the Biochemical Pathways Involved

“…Only genes affected by at least two miRNA pairs were considered. This revealed another five predicted repressed genes ( Tables S1 and S2 in Supplementals S1 ), all of which are involved in fetal development [ 29 , 30 , 31 , 32 , 33 ], and have not ever been associated with FGR before. Three of these miRNA-target genes were associated with specific developmental processes, reinforcing the notion that miR-188-5p and miR-25-3p may have a specific role in FGR.…”