title: An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy.
abstract: Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of re-synthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.
authors: Department of Biochemistry, Medical University of Gdansk, 1 Debinki Str, 80-210 Gdansk, Poland.
authors: Marta
authors: M
authors: Toczek
authors: Department of Social Medicine, Poznan University of Medical Sciences, 6 Rokietnicka Str, 60-806 Poznan, Poland.
authors: Daniel
authors: D
authors: Zielonka
authors: Department of Biochemistry, Medical University of Gdansk, 1 Debinki Str, 80-210 Gdansk, Poland.
authors: Paulina
authors: P
authors: Zukowska
authors: Department of Social Medicine, Poznan University of Medical Sciences, 6 Rokietnicka Str, 60-806 Poznan, Poland.
authors: Jerzy T
authors: JT
authors: Marcinkowski
authors: Department of Biochemistry, Medical University of Gdansk, 1 Debinki Str, 80-210 Gdansk, Poland.
authors: Ewa
authors: E
authors: Slominska
authors: Department of Life Sciences, Imperial College London, Exhibition Road, SW7 2AZ London, UK.
authors: Mark
authors: M
authors: Isalan
authors: Department of Biochemistry, Medical University of Gdansk, 1 Debinki Str, 80-210 Gdansk, Poland. Electronic address: rt.smolenski@gumed.edu.pl.
authors: Ryszard T
authors: RT
authors: Smolenski
authors: Department of Life Sciences, Imperial College London, Exhibition Road, SW7 2AZ London, UK. Electronic address: mielcarekml@gmail.com.
authors: Michal
authors: M
authors: Mielcarek
keywords: Arrhythmia; Cardiomyopathy; Catabolism of nucleotides; Energy imbalance; Heart failure; Huntington's disease