New Insights Into Energy Substrate Utilization and Metabolic Remodeling in Cardiac Physiological Adaption

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  FIGURE 1. The scheme of major mechanisms of exercise-promoted metabolic remodeling in the heart summarized in this review. Exercise can improve cardiac mitochondrial biogenesis through the eNOS signaling pathway that promotes mitochondrial DNA (mtDNA) content, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM). Exercise can also upregulate the phosphorylation level of sucrose non-fermenting AMPK-related kinase (SNARK), enhancing glucose uptake and utilization. Besides, exercise stimulates circulating insulin-like growth factor (IGF-1) and insulin that increase overall glucose transport and uptake and also upregulates serine phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) that boost glycolysis in the heart. In addition, exercise augments the activation of the mammalian target of rapamycin (mTOR) and reduces the activity of glucose 6-phosphate isomerase (GPI). Systemically, exercise can stimulate peripheral fatty acid mobilization from adipose tissue, and increased palmitoleic acid (C16:1n7) stimulates Akt phosphorylation that mediates metabolic…

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  FIGURE 2. Summarization of progress of metabolic remodeling in the developing heart. The developing heart undergoes a unique metabolic switch from the primary utilization of glucose through the glycolytic pathway and auxiliary biosynthetic pathways, including the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP) to fatty acid oxidation as the mitochondrial structure and function mature to substantially improve mitochondrial oxidative capacity. Intermediate metabolites that are specifically increased during proliferation, such as lactate, alanine, succinate, and triglycerides, are markedly decreased during maturation. At the transcriptional level, maturation of cardiomyocytes relies on a sharp decrease in the expression of the hypoxia-inducible factor 1 subunit a (HIF1a), HIF1a-dependent cardiac transcription factor heart, and neural crest-derived transcript-1 (Hand1), and lactate dehydrogenase A (LDHA). Thus, inhibition of the HIF1α/Hand1 and HIF1α/LDHA signaling plays a crucial role in the time-dependent metabolic shift toward increased metabolic flux to the TCA cycle as the predominant metabolic pathway of oxidative metabolism.