Figure 1.

Thyroid hormone and glucocorticoids contribute to the differential metabolism of fetal and adult cardiomyocytes. The predominant ATP generation pathways in the fetal (orange arrows) and adult (blue arrows) cardiomyocytes are shown. The fetal heart primarily relies on glycolysis, with some glucose and lactate oxidation. The adult heart chiefly oxidizes fatty acids but is metabolically flexible. Thyroid hormone in the form of T3 activates TRs α and β directly or downstream of conversion from T4. Upon activation by T3, TRs trigger the expression of several mitochondrial biogenesis, beta-oxidation and electron transport chain related genes. TRβ also promotes oxidative consumption of triglycerides without T3. Glucocorticoid receptor (GR) has similarly been linked to pro-OXPHOS and beta-oxidation pathways in adult CMs and is essential for adult heart function. ATP generated in the mitochondria travels by simple diffusion during development, but creatine kinase (CK) shuttling and direct adenine nucleotide channeling (DANC) ensure rapid transferral in the adult cardiomyocyte to sites of consumption. Abbreviations: ANT, adenine nucleotide translocator; Cr, creatine; PPP, pentose phosphate pathway; F6P, fructose-6-phosphate; β-OX, beta-oxidation; G6P, glucose-6-phosphate; HBP, hexosamine biosynthetic pathway; PCr,

phosphocreatine; TCAC, tricarboxylic acid cycle.