Mechanisms of reduced myocardial energetics of the dystrophic heart.

Heart disease is a leading cause of death in patients with Duchenne muscular dystrophy (DMD), characterized by the progressive replacement of contractile tissue with scar tissue. Effective therapies for dystrophic cardiomyopathy will require addressing the disease before the onset of fibrosis, however, the mechanisms of the early disease are poorly understood. To understand the pathophysiology of DMD, we perform a detailed functional assessment of cardiac function of the mdx mouse, a model of DMD. These studies use a combination of functional, metabolomic, and spectroscopic approaches to fully characterize the contractile, energetic, and mitochondrial function of beating hearts. Through these innovative approaches, we demonstrate that the dystrophic heart has reduced cardiac reserve and is energetically limited. We show that this limitation does not result from poor delivery of oxygen. Using spectroscopic approaches, we provide evidence that mitochondria in the dystrophic heart have attenuated mitochondrial membrane potential and deficits in the flow of electrons in complex IV of the electron transport chain. These studies provide evidence that poor myocardial energetics precede the onset of significant cardiac fibrosis and likely results from mitochondrial dysfunction centered around complex IV and reduced membrane potential. The multimodal approach used here implicates specific molecular components in the etiology of reduced energetics. Future studies focused on these targets may provide therapies that improve the energetics of the dystrophic heart leading to improved resiliency against damage and preservation of myocardial contractile tissue.NEW & NOTEWORTHY Dystrophic hearts have poor contractile reserve that is associated with a reduction in myocardial energetics. We demonstrate that oxygen delivery does not contribute to the limited energy production of the dystrophic heart even with increased workloads. Cytochrome optical spectroscopy of the contracting heart reveals alterations in complex IV and evidence of depolarized mitochondrial membranes. We show specific alterations in the electron transport chain of the dystrophic heart that may contribute to poor myocardial energetics.

A 1H-NMR approach to myocardial energetics.

Understanding the energetic state of the heart is essential for unraveling the central tenets of cardiac physiology. The heart uses a tremendous amount of energy and reductions in that energy supply can have lethal consequences. While ischemic events clearly result in significant metabolic perturbations, heart failure with both preserved and reduced ejection fraction display reductions in energetic status. To date, most cardiac energetics have been performed using 31P-NMR, which requires dedicated access to a specialized NMR spectrometer. This has limited the availability of this method to a handful of centers around the world. Here we present a method of assessing myocardial energetics in the isolated mouse heart using 1H-NMR spectrometers that are widely available in NMR core facilities. In addition, this methodology provides information on many other important metabolites within the heart, including unique metabolic differences between the hypoxic and ischemic hearts. Furthermore, we demonstrate the correlation between myocardial energetics and measures of contractile function in the mouse heart. These methods will allow a broader examination of myocardial energetics providing a valuable tool to aid in the understanding of the nature of these energetic deficits and to develop therapies directed at improving myocardial energetics in failing hearts.