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

Huntington's disease (HD) is a fatal neurodegenerative disorder, caused by a polyglutamine expansion in the huntingtin protein (HTT). HD has a peripheral component to its pathology: skeletal muscles are severely affected, leading to atrophy, and malfunction in both pre-clinical and clinical settings. We previously used two symptomatic HD mouse models to demonstrate the impairment of the contractile characteristics of the hind limb muscles, which was accompanied by a significant loss of function of motor units. The mice displayed a significant reduction in muscle force, likely because of deteriorations in energy metabolism, decreased oxidation, and altered purine metabolism. There is growing evidence suggesting that HD-related skeletal muscle malfunction might be partially or completely independent of CNS degeneration. The pathology might arise from mutant HTT within muscle (loss or gain of function). Hence, it is vital to identify novel peripheral biomarkers that will reflect HD skeletal muscle atrophy. These will be important for upcoming clinical trials that may target HD peripherally. In order to identify potential biomarkers that might reflect muscle metabolic changes, we used qPCR to validate key gene transcripts in different skeletal muscle types. Consequently, we report a number of transcript alterations that are linked to HD muscle pathology.

[1]  A. Wyttenbach,et al.  In Vitro and in Vivo Aggregation of a Fragment of Huntingtin Protein Directly Causes Free Radical Production* , 2011, The Journal of Biological Chemistry.

[2]  M. Isalan,et al.  An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy. , 2016, Biochimica et biophysica acta.

[3]  I. Arinze Facilitating understanding of the purine nucleotide cycle and the one‐carbon pool: Part I: The purine nucleotide cycle , 2005, Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular Biology.

[4]  E. Olson,et al.  Signaling pathways in skeletal muscle remodeling. , 2006, Annual review of biochemistry.

[5]  M. Isalan,et al.  Changes in cardiac nucleotide metabolism in Huntington's disease , 2016, Nucleosides, nucleotides & nucleic acids.

[6]  J. Marcinkowski,et al.  Skeletal muscle pathology in Huntington's disease , 2014, Front. Physiol..

[7]  Thomas H Gillingwater,et al.  Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation , 2004, The European journal of neuroscience.

[8]  M. Russo,et al.  Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects , 2006, Cell Death and Differentiation.

[9]  Mark Turmaine,et al.  Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation , 1997, Cell.

[10]  K. Hoyt,et al.  Cardiac dysfunction in the R6/2 mouse model of Huntington’s disease , 2007, Neurobiology of Disease.

[11]  S. Ayala‐Peña,et al.  Role of oxidative DNA damage in mitochondrial dysfunction and Huntington's disease pathogenesis. , 2013, Free radical biology & medicine.

[12]  G. Bates,et al.  Formation of Polyglutamine Inclusions in a Wide Range of Non-CNS Tissues in the HdhQ150 Knock-In Mouse Model of Huntington's Disease , 2009, PloS one.

[13]  C. Padovani,et al.  Skeletal muscule fiber types in C57BL6J mice , 2004 .

[14]  Y. Kokubo,et al.  Associations of Hypertension and Its Complications with Variations in the Xanthine Dehydrogenase Gene , 2008, Hypertension Research.

[15]  M. Isalan,et al.  Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice , 2012, Proceedings of the National Academy of Sciences.

[16]  Erich E Wanker,et al.  The hunt for huntingtin function: interaction partners tell many different stories. , 2003, Trends in biochemical sciences.

[17]  G. Landwehrmeyer,et al.  Update on Huntington's disease: advances in care and emerging therapeutic options. , 2015, Parkinsonism & related disorders.

[18]  P. Marks,et al.  SAHA Decreases HDAC 2 and 4 Levels In Vivo and Improves Molecular Phenotypes in the R6/2 Mouse Model of Huntington's Disease , 2011, PloS one.

[19]  A. Hannan,et al.  Neurocardiac dysregulation and neurogenic arrhythmias in a transgenic mouse model of Huntington's disease , 2012, The Journal of physiology.

[20]  N. Déglon,et al.  Mitochondria in Huntington's disease. , 2010, Biochimica et biophysica acta.

[21]  M. Isalan,et al.  Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice , 2016, Molecular Neurodegeneration.

[22]  L. Zuo,et al.  Redox Characterization of Functioning Skeletal Muscle , 2015, Front. Physiol..

[23]  M. Isalan,et al.  A shared mechanism of muscle wasting in cancer and Huntington’s disease , 2015, Clinical and Translational Medicine.

[24]  S. W. Davies,et al.  Formation of polyglutamine inclusions in non-CNS tissue. , 1999, Human molecular genetics.

[25]  T. Morisaki,et al.  Subunit composition of AMPD varies in response to changes in AMPD1 and AMPD3 gene expression in skeletal muscle. , 1996, Proceedings of the Association of American Physicians.

[26]  K. Myburgh,et al.  Skeletal muscle wasting with disuse atrophy is multi-dimensional: the response and interaction of myonuclei, satellite cells and signaling pathways , 2014, Front. Physiol..

[27]  L. Greensmith,et al.  HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy , 2015, PLoS genetics.

[28]  G. Bates,et al.  Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease , 2014, PLoS genetics.

[29]  M. Mielcarek Huntington's disease is a multi-system disorder , 2015, Rare diseases.

[30]  L. Fairbanks,et al.  Purine Nucleoside Phosphorylase Deficiency: A Mutation Update , 2011, Nucleosides, nucleotides & nucleic acids.

[31]  Erich E. Wanker,et al.  HDAC4 Reduction: A Novel Therapeutic Strategy to Target Cytoplasmic Huntingtin and Ameliorate Neurodegeneration , 2013, PLoS biology.

[32]  Gilles J Guillemin,et al.  The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease: A Mini Review , 2016, Oxidative medicine and cellular longevity.

[33]  A. Krook,et al.  Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ , 2009, Pharmacological Reviews.

[34]  B. Landwehrmeyer,et al.  Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease , 2005, Movement disorders : official journal of the Movement Disorder Society.

[35]  W. Roberts,et al.  Characterization of reactive oxygen species in diaphragm , 2015, Acta physiologica.

[36]  S. Folstein,et al.  Huntington's disease gene (IT15) is widely expressed in human and rat tissues , 1993, Neuron.

[37]  M. Vinciguerra,et al.  Regulation of muscle atrophy in aging and disease. , 2010, Advances in experimental medicine and biology.

[38]  Carlo Reggiani,et al.  Fiber types in mammalian skeletal muscles. , 2011, Physiological reviews.

[39]  L. Zuo,et al.  Redox Roles of Reactive Oxygen Species in Cardiovascular Diseases , 2015, International journal of molecular sciences.