Return to the fetal gene program: a suggested metabolic link to gene expression in the heart

Abstract

A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. After birth, energy substrate metabolism rapidly switches to the oxidation of fatty acids. This switch accompanies the expression of "adult" isoforms of metabolic enzymes and other proteins. However, in a variety of pathophysiologic conditions, including hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the postnatal heart returns to the "fetal" gene program. These adaptive mechanisms are also a feature of the failing heart muscle, where at a certain point this fetal-like reprogramming no longer suffices to support cardiac structure and function. We advance the hypothesis that in the postnatal heart, metabolic remodeling triggers the process through glycosylation of transcription factors, potentially protecting the stressed heart from irreversible functional impairment and programmed cell death. In other words, we propose a metabolic link to gene expression in the heart.

Figure 1

Transmission electron micrograph of mammalian left ventricular myocardium from (A) a 5-month-old human fetus and (B) an adult dog. (A) Note the vast number of large, highly-branched molecules of glycogen, which appear as very dark cytoplasmic granules found mostly in the form of β-granules (scan courtesy of Dr. Visvan Navaratnam, University of Cambridge, UK). Also note (B) the large number of mitochondia in the adult canine myocardium at 1:1800 magnification (scan courtesy of Dr. Barry Van Winkle, University of Texas Health Science Center at Houston).

Figure 2

Proposed mechanism of metabolic remodeling. Under a wide spectrum of stressors (pressure overload, unloading, ischemia, diabetes), the heart alters its metabolism and uses less commonly used pathways (hexosamine biosynthetic pathway), leading to an accumulation of metabolic signals that triggers the induction of the fetal gene program. (Modified from Young et al. )

Figure 3

Proposed mechanism of altered glucose homeostasis leading to changes in gene expression. When excess glucose is presented to hearts under certain environmental stressors (pressure overload, unloading, ischemia, diabetes), glucose homeostasis is altered. Excess glucose enters the glycolytic pathway, but it also may be stored as glycogen or shunted into the hexosamine biosynthetic pathway leading to protein glycosylation of transcription factors, inducing the return to the fetal gene program to protect the heart. (Modified from Young et al.)

Figure 4

Effects of altered carbohydrate and fat availability on mhc α (A) and mhc β (B) expression, and on the ratio of mhc α/mhc β (C) in hypertrophied (banded) rat hearts. Rats were placed on either a high-carbohydrate/low-fat (HC/LF) diet or on a low-carbohydrate/high-fat (LC/HF) diet. (Adapted from Young et al.)