The role of cardiac energy metabolism in cardiac hypertrophy and failure
Introduction
The mechanical pumping function of the heart provides sufficient and constant flow of oxygen and nutrients to itself and other tissues in the mammalian body. To secure the availability of energy substrates, heart has developed into a “multifuel” organ able to use fatty acids, glucose, lactate, amino acids and ketone bodies as a source of energy. In a healthy heart, production of cellular energy (ATP) in cardiac muscle cells relies heavily on mitochondrial oxidative phosphorylation fuelled mainly by fatty acid oxidation and to lesser extent on glucose oxidation or glycolysis. Cardiac metabolism has wide adaptive capacity and plasticity when facing conditions that challenge heart energy production. However, most forms of cardiac diseases are associated with maladaptive changes in energy metabolism exacerbating the disease progression. Development of pathological hypertrophy and concomitant heart failure are associated with reduced contractile function in parallel with shift in energy substrate preference from fatty acids to glucose and gradual decline of mitochondrial oxidative phosphorylation. Here we discuss how cardiac energy metabolism and maladaptive metabolic alterations are associated with cardiac disease. Further, we highlight some of the mechanisms and transcriptional pathways linking hypertrophy and contractile function to energy metabolism in the development of heart failure.
Section snippets
Sources and sinks of cardiac energy
In the mammalian embryo, proliferating cardiomyocyte precursor cells are dependent on glycolysis as a source of energy, while mitochondrial organization and oxidative metabolism are poorly developed [1]. Although the heart develops in a low oxygen environment and high rates of glycolysis and lactate production are typical, fetal hearts are still able to oxidise lactate and fatty acids. However, oxidation contributes only a minor fraction of the total ATP production (~15%) [2]. As cardiomyocytes
Metabolic changes in cardiac hypertrophy and failure
Metabolic remodelling is associated with most, if not all types of cardiac pathologies. However, the types of metabolic alterations depend on the type of cardiac disease. Pathological hypertrophy and ischemic heart disease both involve reduced oxidative metabolism, whereas diabetic cardiomyopathy results in increase of fatty acid oxidation due to their increased circulating levels [9]. However, in all of these conditions metabolic changes lead to increase in the oxygen consumption/produced
Transcriptional control of cardiac energy metabolism
To avoid acute energy deprivation cells possess mechanisms serving as safeguards between production and demand of ATP. Adenosine monophosphate-activated protein kinase (AMPK) acts as a central sensor of cellular energy status, responding to short term changes in available energy. Activation of AMPK by an increase in AMP/ATP-ratio promotes changes aimed at restoring ATP levels, mainly by increasing glucose catabolism [19]. While activation of AMPK acutely secure cardiac energy supply it merely
Crosstalk between energy metabolism and cardiomyocyte function
Cardiac hypertrophy involves remodelling of gene expression, which eventually leads to drastic alterations in cardiac function parallel with the changes in cardiac metabolism. Pathological hypertrophy is associated with changes in energy substrate uptake and utilisation, as well as mitochondrial oxidative metabolism, eventually leading to compromised energy availability in the failing heart (Fig. 1). It is, however, unclear whether metabolic changes predispose heart to functional alterations or
Conclusion
Cardiac muscle adaptations to increased energy demand or compromised energy supply involve coordinated remodelling of the expression of networks of the genes, as well as translational and posttranslational modifications of proteins involved in the short and long-term adaptation. Metabolic adaptation involves several parallel and overlapping signalling cascades regulating energy substrate specificity and utilisation, use and delivery of oxygen and mitochondrial function. These mechanisms are
Conflict of interest
The authors have no conflicts to declare.
Acknowledgments
This work was supported by the Academy of Finland (P.T.; Grant no. 267637), the Sigrid Juselius Foundation, the Finnish Foundation for Cardiovascular Research.
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