Changes in cardiac nucleotide metabolism in Huntington's disease

Abstract

Huntington's disease (HD) is a monogenic neurodegenerative disorder with a significant peripheral component to the disease pathology. This includes an HD-related cardiomyopathy, with an unknown pathological mechanism. In this study, we aimed to define changes in the metabolism of cardiac nucleotides using the well-established R6/2 mouse model. In particular, we focused on measuring the activity of enzymes that control ATP and other adenine nucleotides in the cardiac pool, including eNTPD, AMPD, e5'NT, ADA, and PNP. We employed HPLC to assay the activities of these enzymes by measuring the concentrations of adenine nucleotide catabolites in the hearts of symptomatic R6/2 mice. We found a reduced activity of AMPD (12.9 ± 1.9 nmol/min/mg protein in control; 7.5 ± 0.5 nmol/min/mg protein in R6/2) and e5'NT (11.9 ± 1.7 nmol/min/mg protein in control; 6.7 ± 0.7 nmol/min/mg protein in R6/2). Moreover, we detected an increased activity of ADA (1.3 ± 0.2 nmol/min/mg protein in control; 5.2 ± 0.5 nmol/min/mg protein in R6/2), while no changes in eNTPD and PNP activities were observed. Analysis of cardiac adenine nucleotide catabolite levels revealed an increased inosine level (0.7 ± 0.01 nmol/mg dry tissue in control; 2.7 ±0.8 nmol/mg dry tissue in R6/2) and a reduced concentration of cardiac adenosine (0.9 ± 0.2 nmol/mg dry tissue in control; 0.2 ± 0.08 nmol/mg dry tissue in R6/2). This study highlights a decreased rate of degradation of cardiac nucleotides in HD mouse model hearts, and an increased capacity for adenosine deamination, that may alter adenosine signaling.

Transcriptional Signature of an Altered Purine Metabolism in the Skeletal Muscle of a Huntington's Disease Mouse Model

“…Consequently, it has been shown that these cardiac pathologies might be caused by significant alterations in mitochondrial structure, including the loss of mitochondrial elongated shapes and diffused mitochondrial densities (Mihm et al, 2007 ; Kiriazis et al, 2012 ). Supporting this view of altered mitochondrial energy metabolism, we observed an increased level of purine catabolites in the heart mass of HD mouse models (Toczek et al, 2016a , b ). In addition, reactive oxygen species (ROS) play an important role in mitochondrial dysfunction, especially in skeletal muscle atrophy (Zuo et al, 2015 ; Zuo and Pannell, 2015 ) and heart failure (He and Zuo, 2015 ).…”

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

“…In fact we showed that these catabolites were accumulated within the heart mass in the R6/2 mouse model [58]. In addition, these findings are supported by the observation of the up-regulation of genes involved in the adenosine degradation pathway, such as Ada or Dpp4.…”

Neuro-Cardio Mechanisms in Huntington’s Disease and Other Neurodegenerative Disorders

“…These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD, in both pre-clinical and clinical settings ( Toczek et al, 2016b ). High-performance liquid chromatography assays demonstrate that enzymatic activity is also affected; AMPD and e5′NT exhibit decreased activity whereas ADA activity levels are increased, suggesting that mutant HTT could be disrupting cardiac nucleotide metabolism on a transcriptional level ( Toczek et al, 2016a ). Importantly, mutant HTT interacts with global gene regulators, such as HDACs, and this is potentially important for the gene expression changes observed in HD, as well as other types of cardiomyopathies ( Mielcarek et al, 2013 , 2015b ; Piotrowska et al, 2017 ).…”