Cardiac maturation

Abstract

The heart undergoes a dynamic maturation process following birth, in response to a wide range of stimuli, including both physiological and pathological cues. This process entails substantial re-programming of mitochondrial energy metabolism coincident with the emergence of specialized structural and contractile machinery to meet the demands of the adult heart. Many components of this program revert to a more "fetal" format during development of pathological cardiac hypertrophy and heart failure. In this review, emphasis is placed on recent progress in our understanding of the transcriptional control of cardiac maturation, encompassing the results of studies spanning from in vivo models to cardiomyocytes derived from human stem cells. The potential applications of this current state of knowledge to new translational avenues aimed at the treatment of heart failure is also addressed.

Keywords: Cardiomyocyte maturation; Fetal gene program; Gene transcription; Mitochondrial metabolism; Nuclear receptor; Postnatal development.

Figure 1.. Coordinated Cardiac Structural, Contractile, and Mitochondrial Metabolic Maturation

The illustration in Figure 1 highlights the intricate maturation processes observed during the lifespan of the mammalian heart. The fetal heart relies largely on glucose and lactate as the preferred energy substrates. However, during the perinatal period a mitochondrial biogenic response is followed by a maturation process that equips the heart with high capacity for fatty acid oxidation and a substrate preference switch from carbohydrates to fatty acids. In healthy adult hearts, fatty acids are the primary source for energy production, with over 95% of ATP synthesis occurring through oxidative phosphorylation within the mitochondria. The maturation of mitochondrial metabolism is accompanied by distinct transitions from fetal to adult isoform contractile protein expression, along with a significant augmentation of Ca²⁺ handling and ion transport machinery. Contractile protein isoform switching is largely completed by ~9 months in human heart and by postnatal day 21 (P21) in mouse hearts based on troponin I expression switching. During the development of heart failure, a so-called “fetal gene program” is re-activated in adult CMs, marked by a decline in adult cardiac gene expression and concurrent induction of a subset of fetal cardiac genes. The control of cell proliferative activity also undergoes substantial regulation during the developmental process, with fetal CMs displaying robust proliferative capacity. However, as development proceeds after birth, the vast majority of CMs exit the cell cycle, culminating in their transformation into fully differentiated, mature CMs.

Figure 2.. Regulation of PGC-1α Activity and Transcriptional Co-activation in Mitochondrial Energy Metabolism.

PGC-1α expression and activity are modulated by a network of signaling pathways and transcription factors as indicated. PGC-1α serves as a central co-activator by directly interacting with various transcriptional regulators, including nuclear receptors, to modulate the expression of genes involved in mitochondrial oxidative metabolism. Of particular significance, the Estrogen-Related Receptor (ERR) is highlighted as a master regulator governing multiple facets of mitochondrial energy metabolism, encompassing fatty acid oxidation, oxidative phosphorylation (OXPHOS), tricarboxylic acid (TCA) cycle, and mitochondrial biogenesis. PERM1 coactivates PGC-1α/ERR and PGC-1α/PPAR transcriptional events but it has distinct functions in mitochondria and cytoplasm to facilitate mitochondrial metabolism. In the figure, red dotted lines represent activation of activity, red solid lines signify activation of transcription, black dotted lines depict fatty acid ligands binding to the indicated nuclear receptors, and blue dotted lines depict deactivation of activity.

Figure 3.. The Cardiac Fetal-to-Adult Contractile Isoform Transition.

Postnatal development is marked by significant shifts and switches in the expression of sarcomere proteins isoforms, driven primarily by a combination of transcriptional and posttranscriptional regulatory processes. Well-described gene isoform changes are depicted.

Figure 4.. Coordinate transcriptional control of energy metabolic and contractile maturation by the ERR/PGC-1α complex.

ERR has emerged as a significant regulator of cardiac gene transcription in the adult heart. ERRα and γ occupy numerous cardiac promoters and enhancer regions in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), characterized by H3K27ac deposition. The functional collaboration between ERR and GATA4 is prominently evident in the regulation of cardiac-specific genes that encode components of the cardiac sarcomere, ion transport proteins, calcium handling proteins, and natriuretic peptides. In contrast, ERRs regulate canonical energy metabolic genes independent of cardiogenic transcription factors. PGC-1 serves as a coactivator of both mechanisms. This mechanism serves to regulate mitochondrial ATP-producing and downstream contractile and ion transport processes in a coordinate manner during cardiomyocyte maturation.