https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=31278192&retmode=xml&tool=Litmetric&email=readroberts32@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09 312781922020050520200505
1754-84111272019Jul26Disease models & mechanismsDis Model MechDeterioration of mitochondrial bioenergetics and ultrastructure impairment in skeletal muscle of a transgenic minipig model in the early stages of Huntington's disease.dmm03873710.1242/dmm.038737Skeletal muscle wasting and atrophy is one of the more severe clinical impairments resulting from the progression of Huntington's disease (HD). Mitochondrial dysfunction may play a significant role in the etiology of HD, but the specific condition of mitochondria in muscle has not been widely studied during the development of HD. To determine the role of mitochondria in skeletal muscle during the early stages of HD, we analyzed quadriceps femoris muscle from 24-, 36-, 48- and 66-month-old transgenic minipigs that expressed the N-terminal portion of mutated human huntingtin protein (TgHD) and age-matched wild-type (WT) siblings. We found altered ultrastructure of TgHD muscle tissue and mitochondria. There was also significant reduction of activity of citrate synthase and respiratory chain complexes (RCCs) I, II and IV, decreased quantity of oligomycin-sensitivity conferring protein (OSCP) and the E2 subunit of pyruvate dehydrogenase (PDHE2), and differential expression of optic atrophy 1 protein (OPA1) and dynamin-related protein 1 (DRP1) in the skeletal muscle of TgHD minipigs. Statistical analysis identified several parameters that were dependent only on HD status and could therefore be used as potential biomarkers of disease progression. In particular, the reduction of biomarker RCCII subunit SDH30 quantity suggests that similar pathogenic mechanisms underlie disease progression in TgHD minipigs and HD patients. The perturbed biochemical phenotype was detectable in TgHD minipigs prior to the development of ultrastructural changes and locomotor impairment, which become evident at the age of 48 months. Mitochondrial disturbances may contribute to energetic depression in skeletal muscle in HD, which is in concordance with the mobility problems observed in this model.This article has an associated First Person interview with the first author of the paper.© 2019. Published by The Company of Biologists Ltd.RodinovaMarieMLaboratory for Study of Mitochondrial Disorders, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague 2, Czech Republic.KrizovaJanaJ0000-0003-1841-7341Laboratory for Study of Mitochondrial Disorders, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague 2, Czech Republic.StufkovaHanaHLaboratory for Study of Mitochondrial Disorders, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague 2, Czech Republic.BohuslavovaBozenaB0000-0002-9415-5139Laboratory of Cell Regeneration and Cell Plasticity, Institute of Animal Physiology and Genetics AS CR, 27721 Liběchov, Czech Republic.AskelandGeorginaG0000-0001-8532-8029Department of Medical Biochemistry, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway.DosoudilovaZanetaZLaboratory for Study of Mitochondrial Disorders, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague 2, Czech Republic.JuhasStefanS0000-0002-2866-0727Laboratory of Cell Regeneration and Cell Plasticity, Institute of Animal Physiology and Genetics AS CR, 27721 Liběchov, Czech Republic.JuhasovaJanaJ0000-0001-7022-6812Laboratory of Cell Regeneration and Cell Plasticity, Institute of Animal Physiology and Genetics AS CR, 27721 Liběchov, Czech Republic.EllederovaZdenkaZ0000-0001-6695-6345Laboratory of Cell Regeneration and Cell Plasticity, Institute of Animal Physiology and Genetics AS CR, 27721 Liběchov, Czech Republic.ZemanJiriJ0000-0002-2678-7919Laboratory for Study of Mitochondrial Disorders, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague 2, Czech Republic.EideLarsL0000-0003-3948-5183Department of Medical Biochemistry, University of Oslo and Oslo University Hospital, 0372 Oslo, Norway.MotlikJanJLaboratory of Cell Regeneration and Cell Plasticity, Institute of Animal Physiology and Genetics AS CR, 27721 Liběchov, Czech Republic.HansikovaHanaH0000-0002-2734-225XLaboratory for Study of Mitochondrial Disorders, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 12108 Prague 2, Czech Republic hana.hansikova@lf1.cuni.cz.engJournal ArticleResearch Support, Non-U.S. Gov't20190726
EnglandDis Model Mech1014833321754-84030HTT protein, human0Huntingtin Protein0Mitochondrial Proteins9007-49-2DNAIMAnimalsAnimals, Genetically ModifiedBody WeightDNAmetabolismDisease Models, AnimalDisease ProgressionElectron TransportEnergy MetabolismHumansHuntingtin ProteingeneticsHuntington DiseasemetabolismpathologyMitochondria, MusclemetabolismultrastructureMitochondrial ProteinsmetabolismMuscle, SkeletalmetabolismultrastructureMutationOxidative PhosphorylationSwineSwine, MiniatureBiomarkersDisease developmentHD large animal modelHuntington's diseaseMitochondrial functionSkeletal muscleUltrastructureCompeting interestsThe authors declare no competing or financial interests.20191320196182019776020205660201977602019726epublish31278192PMC667938510.1242/dmm.038737dmm.038737Antoniel M., Giorgio V., Fogolari F., Glick G. D., Bernardi P. and Lippe G. (2014). The oligomycin-sensitivity conferring protein of mitochondrial ATP synthase: emerging new roles in mitochondrial pathophysiology. Int. J. Mol. Sci. 15, 7513-7536. 10.3390/ijms1505751310.3390/ijms15057513PMC405768724786291Arenas J., Campos Y., Ribacoba R., Martín M. A., Rubio J. C., Ablanedo P. and Cabello A. (1998). Complex I defect in muscle from patients with Huntington's disease. Ann. Neurol. 43, 397-400. 10.1002/ana.41043032110.1002/ana.4104303219506560Askeland G., Dosoudilova Z., Rodinova M., Klempir J., Liskova I., Kuśnierczyk A., Bjørås M., Nesse G., Klungland A., Hansikova H. et al. (2018a). Increased nuclear DNA damage precedes mitochondrial dysfunction in peripheral blood mononuclear cells from Huntington's disease patients. Sci. Rep. 8, 9817 10.1038/s41598-018-27985-y10.1038/s41598-018-27985-yPMC602614029959348Askeland G., Rodinova M., Štufková H., Dosoudilova Z., Baxa M., Smatlikova P., Bohuslavova B., Klempir J., Nguyen T. D., Kuśnierczyk A. et al. (2018b). A transgenic minipig model of Huntington's disease shows early signs of behavioral and molecular pathologies. Dis. Model. Mech. 11, dmm035949 10.1242/dmm.03594910.1242/dmm.035949PMC621542830254085Baldwin K. M., Hooker A. M. and Herrick R. E. (1978). Lactate oxidative capacity in different types of muscle. Biochem. Biophys. Res. Commun. 83, 151-157. 10.1016/0006-291X(78)90410-210.1016/0006-291X(78)90410-2697805Banoei M. M., Houshmand M., Panahi M. S. S., Shariati P., Rostami M., Manshadi M. D. and Majidizadeh T. (2007). Huntington's disease and mitochondrial DNA deletions: event or regular mechanism for mutant huntingtin protein and CAG repeats expansion?! Cell. Mol. Neurobiol. 27, 867-875. 10.1007/s10571-007-9206-510.1007/s10571-007-9206-517952586Baxa M., Hruska-Plochan M., Juhas S., Vodicka P., Pavlok A., Juhasova J., Miyanohara A., Nejime T., Klima J., Macakova M. et al. (2013). A transgenic minipig model of Huntington's Disease. J. Huntingtons Dis. 2, 47-68. 10.3233/JHD-13000110.3233/JHD-13000125063429Beck S. J., Guo L., Phensy A., Tian J., Wang L., Tandon N., Gauba E., Lu L., Pascual J. M., Kroener S. et al. (2016). Deregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer's disease. Nat. Commun. 7, 11483 10.1038/ncomms1148310.1038/ncomms11483PMC549419727151236Benchoua A., Trioulier Y., Zala D., Gaillard M.-C., Lefort N., Dufour N., Saudou F., Elalouf J.-M., Hirsch E., Hantraye P. et al. (2006). Involvement of mitochondrial complex II defects in neuronal death produced by N-terminus fragment of mutated huntingtin. Mol. Biol. Cell 17, 1652-1663. 10.1091/mbc.e05-07-060710.1091/mbc.e05-07-0607PMC141530516452635Bradford M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254. 10.1016/0003-2697(76)90527-310.1016/0003-2697(76)90527-3942051Buck E., Zügel M., Schumann U., Merz T., Gumpp A. M., Witting A., Steinacker J. M., Landwehrmeyer G. B., Weydt P., Calzia E. et al. (2017). High-resolution respirometry of fine-needle muscle biopsies in pre-manifest Huntington's disease expansion mutation carriers shows normal mitochondrial respiratory function. PLoS ONE 12, e0175248 10.1371/journal.pone.017524810.1371/journal.pone.0175248PMC539099728406926Busse M. E., Hughes G., Wiles C. M. and Rosser A. E. (2008). Use of hand-held dynamometry in the evaluation of lower limb muscle strength in people with Huntington's disease. J. Neurol. 255, 1534-1540. 10.1007/s00415-008-0964-x10.1007/s00415-008-0964-x19005627Cahova M., Chrastina P., Hansikova H., Drahota Z., Trnovska J., Skop V., Spacilova J., Malinska H., Oliyarnyk O., Papackova Z. et al. (2015). Carnitine supplementation alleviates lipid metabolism derangements and protects against oxidative stress in non-obese hereditary hypertriglyceridemic rats. Appl. Physiol. Nutr. Metab. 40, 280-291. 10.1139/apnm-2014-016310.1139/apnm-2014-016325723909Carroll J. B., Bates G. P., Steffan J., Saft C. and Tabrizi S. J. (2015). Treating the whole body in Huntington's disease. Lancet Neurol. 14, 1135-1142. 10.1016/S1474-4422(15)00177-510.1016/S1474-4422(15)00177-526466780Cherubini M. and Ginés S. (2017). Mitochondrial fragmentation in neuronal degeneration: toward an understanding of HD striatal susceptibility. Biochem. Biophys. Res. Commun. 483, 1063-1068. 10.1016/j.bbrc.2016.08.04210.1016/j.bbrc.2016.08.04227514446Ciammola A., Sassone J., Alberti L., Meola G., Mancinelli E., Russo M. A., Squitieri F. and Silani V. (2006). Increased apoptosis, Huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects. Cell Death Differ. 13, 2068-2078. 10.1038/sj.cdd.440196710.1038/sj.cdd.440196716729030Ciammola A., Sassone J., Sciacco M., Mencacci N. E., Ripolone M., Bizzi C., Colciago C., Moggio M., Parati G., Silani V. et al. (2011). Low anaerobic threshold and increased skeletal muscle lactate production in subjects with Huntington's disease. Mov. Disord. 26, 130-137. 10.1002/mds.2325810.1002/mds.23258PMC308114120931633Fornuskova D., Stiburek L., Wenchich L., Vinsova K., Hansikova H. and Zeman J. (2010). Novel insights into the assembly and function of human nuclear-encoded cytochrome c oxidase subunits 4, 5a, 6a, 7a and 7b. Biochem. J. 428, 363-374. 10.1042/BJ2009171410.1042/BJ2009171420307258Gao J., Wang L., Liu J., Xie F., Su B. and Wang X. (2017). Abnormalities of mitochondrial dynamics in neurodegenerative diseases. Antioxidants 6, 25 10.3390/antiox602002510.3390/antiox6020025PMC548800528379197Gizatullina Z. Z., Lindenberg K. S., Harjes P., Chen Y., Kosinski C. M., Landwehrmeyer B. G., Ludolph A. C., Striggow F., Zierz S. and Gellerich F. N. (2006). Low stability of Huntington muscle mitochondria against Ca2+ in R6/2 mice. Ann. Neurol. 59, 407-411. 10.1002/ana.2075410.1002/ana.2075416437579Hering T., Kojer K., Birth N., Hallitsch J., Taanman J.-W. and Orth M. (2017). Mitochondrial cristae remodelling is associated with disrupted OPA1 oligomerisation in the Huntington's disease R6/2 fragment model. Exp. Neurol. 288, 167-175. 10.1016/j.expneurol.2016.10.01710.1016/j.expneurol.2016.10.01727889468Horton T. M., Graham B. H., Corral-Debrinski M., Shoffner J. M., Kaufman A. E., Beal M. F. and Wallace D. C. (1995). Marked increase in mitochondrial DNA deletion levels in the cerebral cortex of Huntington's disease patients. Neurology 45, 1879-1883. 10.1212/WNL.45.10.187910.1212/WNL.45.10.18797477986Hu C., Huang Y. and Li L. (2017). Drp1-dependent mitochondrial fission plays critical roles in physiological and pathological progresses in mammals. Int. J. Mol. Sci. 18, 144 10.3390/ijms1801014410.3390/ijms18010144PMC529777728098754Janssen A. J. M., Trijbels F. J., Sengers R. C., Wintjes L. T., Ruitenbeek W., Smeitink J. A., Morava E., van Engelen B. G., van den Heuvel L. P. and Rodenburg R. J. (2006). Measurement of the energy-generating capacity of human muscle mitochondria: diagnostic procedure and application to human pathology. Clin. Chem. 52, 860-871. 10.1373/clinchem.2005.06241410.1373/clinchem.2005.06241416543390Kosinski C. M., Schlangen C., Gellerich F. N., Gizatullina Z., Deschauer M., Schiefer J., Young A. B., Landwehrmeyer G. B., Toyka K. V., Sellhaus B. et al. (2007). Myopathy as a first symptom of Huntington's disease in a Marathon runner. Mov. Disord. 22, 1637-1640. 10.1002/mds.2155010.1002/mds.2155017534945Kremer B., Goldberg P., Andrew S. E., Theilmann J., Telenius H., Zeisler J., Squitieri F., Lin B., Bassett A., Almqvist E. et al. (1994). A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. N. Engl. J. Med. 330, 1401-1406. 10.1056/NEJM19940519330200110.1056/NEJM1994051933020018159192Krizova J., Stufkova H., Rodinova M., Macakova M., Bohuslavova B., Vidinska D., Klima J., Ellederova Z., Pavlok A., Howland D. S. et al. (2017). Mitochondrial metabolism in a large-animal model of huntington disease: the hunt for biomarkers in the spermatozoa of presymptomatic minipigs. Neurodegener. Dis. 17, 213-226. 10.1159/00047546710.1159/00047546728633139Kuznetsov A. V., Veksler V., Gellerich F. N., Saks V., Margreiter R. and Kunz W. S. (2008). Analysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells. Nat. Protoc. 3, 965-976. 10.1038/nprot.2008.6110.1038/nprot.2008.6118536644Liu C.-S., Cheng W.-L., Kuo S.-J., Li J.-Y., Soong B.-W. and Wei Y.-H. (2008). Depletion of mitochondrial DNA in leukocytes of patients with poly-Q diseases. J. Neurol. Sci. 264, 18-21. 10.1016/j.jns.2007.07.01610.1016/j.jns.2007.07.01617720200Lodi R., Schapira A. H. V., Manners D., Styles P., Wood N. W., Taylor D. J. and Warner T. T. (2000). Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy. Ann. Neurol. 48, 72-76. 10.1002/1531-8249(200007)48:1<72::AID-ANA11>3.0.CO;2-I10.1002/1531-8249(200007)48:1<72::AID-ANA11>3.0.CO;2-I10894218Lowry O. H., Rosebrough N. J., Farr A. L. and Randall R. J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265-275.14907713Lund J., Aas V., Tingstad R. H., van Hees A. and Nikolić N. (2018). Utilization of lactic acid in human myotubes and interplay with glucose and fatty acid metabolism. Sci. Rep. 8, 9814 10.1038/s41598-018-28249-510.1038/s41598-018-28249-5PMC602612329959350Macakova M., Bohuslavova B., Vochozkova P., Pavlok A., Sedlackova M., Vidinska D., Vochyanova K., Liskova I., Valekova I., Baxa M. et al. (2016). Mutated Huntingtin causes testicular pathology in transgenic minipig boars. Neurodegener. Dis. 16, 245-259. 10.1159/00044366510.1159/00044366526959244Mantovani S., Gordon R., Li R., Christie D. C., Kumar V. and Woodruff T. M. (2016). Motor deficits associated with Huntington's disease occur in the absence of striatal degeneration in BACHD transgenic mice. Hum. Mol. Genet. 25, 1780-1791. 10.1093/hmg/ddw05010.1093/hmg/ddw05026908618Mielcarek M., Toczek M., Smeets C. J. L. M., Franklin S. A., Bondulich M. K., Jolinon N., Muller T., Ahmed M., Dick J. R. T., Piotrowska I. et al. (2015). HDAC4-myogenin axis as an important marker of HD-related skeletal muscle atrophy. PLoS Genet. 11, e1005021 10.1371/journal.pgen.100502110.1371/journal.pgen.1005021PMC435204725748626Mosca F., Fattorini D., Bompadre S. and Littarru G. P. (2002). Assay of coenzyme Q(10) in plasma by a single dilution step. Anal. Biochem. 305, 49-54. 10.1006/abio.2002.565310.1006/abio.2002.565312018945Munsie L., Caron N., Atwal R. S., Marsden I., Wild E. J., Bamburg J. R., Tabrizi S. J. and Truant R. (2011). Mutant huntingtin causes defective actin remodeling during stress: defining a new role for transglutaminase 2 in neurodegenerative disease. Hum. Mol. Genet. 20, 1937-1951. 10.1093/hmg/ddr07510.1093/hmg/ddr075PMC308060621355047Novak M. J. U. and Tabrizi S. J. (2010). Huntington's disease. BMJ 340, c3109 10.1136/bmj.c310910.1136/bmj.c310920591965Pandey M., Varghese M., Sindhu K. M., Sreetama S., Navneet A. K., Mohanakumar K. P. and Usha R. (2008). Mitochondrial NAD+-linked State 3 respiration and complex-I activity are compromised in the cerebral cortex of 3-nitropropionic acid-induced rat model of Huntington's disease. J. Neurochem. 104, 420-434. 10.1111/j.1471-4159.2007.04996.x10.1111/j.1471-4159.2007.04996.x17953654Panov A. V., Gutekunst C.-A., Leavitt B. R., Hayden M. R., Burke J. R., Strittmatter W. J. and Greenamyre J. T. (2002). Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat. Neurosci. 5, 731-736. 10.1038/nn88410.1038/nn88412089530Petersen M. H., Budtz-Jørgensen E., Sørensen S. A., Nielsen J. E., Hjermind L. E., Vinther-Jensen T., Nielsen S. M. B. and Nørremølle A. (2014). Reduction in mitochondrial DNA copy number in peripheral leukocytes after onset of Huntington's disease. Mitochondrion 17, 14-21. 10.1016/j.mito.2014.05.00110.1016/j.mito.2014.05.00124836434Quintanilla R. A., Jin Y. N., von Bernhardi R. and Johnson G. V. W. (2013). Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Mol. Neurodegener. 8, 45 10.1186/1750-1326-8-4510.1186/1750-1326-8-45PMC387884024330821Reddy P. H. (2014). Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission. Drug Discov. Today 19, 951-955. 10.1016/j.drudis.2014.03.02010.1016/j.drudis.2014.03.020PMC419165724681059Roe A. J. and Qi X. (2018). Drp1 phosphorylation by MAPK1 causes mitochondrial dysfunction in cell culture model of Huntington's disease. Biochem. Biophys. Res. Commun. 496, 706-711. 10.1016/j.bbrc.2018.01.11410.1016/j.bbrc.2018.01.114PMC605784429397067Romanello V., Guadagnin E., Gomes L., Roder I., Sandri C., Petersen Y., Milan G., Masiero E., DEL Piccolo P., Foretz M. et al. (2010). Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 29, 1774-1785. 10.1038/emboj.2010.6010.1038/emboj.2010.60PMC287696520400940Rötig A., de Lonlay P., Chretien D., Foury F., Koenig M., Sidi D., Munnich A. and Rustin P. (1997). Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat. Genet. 17, 215-217. 10.1038/ng1097-21510.1038/ng1097-2159326946Rustin P., Chretien D., Bourgeron T., Gérard B., Rötig A., Saudubray J. M. and Munnich A. (1994). Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chim. Acta 228, 35-51. 10.1016/0009-8981(94)90055-810.1016/0009-8981(94)90055-87955428Rustin P., Munnich A. and Rötig A. (2002). Succinate dehydrogenase and human diseases: new insights into a well-known enzyme. Eur. J. Hum. Genet. 10, 289-291. 10.1038/sj.ejhg.520079310.1038/sj.ejhg.520079312082502Schägger H. and von Jagow G. (1991). Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal. Biochem. 199, 223-231. 10.1016/0003-2697(91)90094-A10.1016/0003-2697(91)90094-A1812789She P., Zhang Z., Marchionini D., Diaz W. C., Jetton T. J., Kimball S. R., Vary T. C., Lang C. H. and Lynch C. J. (2011). Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease. Am. J. Physiol. Endocrinol. Metab. 301, E49-E61. 10.1152/ajpendo.00630.201010.1152/ajpendo.00630.2010PMC312984421505144Silva A. C., Almeida S., Laço M., Duarte A. I., Domingues J., Oliveira C. R., Januário C. and Rego A. C. (2013). Mitochondrial respiratory chain complex activity and bioenergetic alterations in human platelets derived from pre-symptomatic and symptomatic Huntington's disease carriers. Mitochondrion 13, 801-809. 10.1016/j.mito.2013.05.00610.1016/j.mito.2013.05.00623707479Squitieri F., Falleni A., Cannella M., Orobello S., Fulceri F., Lenzi P. and Fornai F. (2010). Abnormal morphology of peripheral cell tissues from patients with Huntington disease. J Neural Transm (Vienna) 117, 77-83. 10.1007/s00702-009-0328-410.1007/s00702-009-0328-419834779Srere D. (1969). [1] Citrate synthase. [EC 4.1.3.7. Citrate oxaloacetate-lyase (CoA-acetylating)]. Methods Enzymol. 13(C), 3-11. 10.1016/0076-6879(69)13005-010.1016/0076-6879(69)13005-0Tabrizi S. J., Workman J., Hart P. E., Mangiarini L., Mahal A., Bates G., Cooper J. M. and Schapira A. H. V. (2000). Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann. Neurol. 47, 80-86. 10.1002/1531-8249(200001)47:1<80::AID-ANA13>3.0.CO;2-K10.1002/1531-8249(200001)47:1<80::AID-ANA13>3.0.CO;2-K10632104Trottier Y., Devys D., Imbert G., Saudou F., An I., Lutz Y., Weber C., Agid Y., Hirsch E. C. and Mandel J.-L. (1995). Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat. Genet. 10, 104-110. 10.1038/ng0595-10410.1038/ng0595-1047647777Tyler D. D. (1992). The Mitochondrion in Health and Disease. VCH Publishers: Weinheim, New York.Valadão P. A. C., de Aragão B. C., Andrade J. N., Magalhães-Gomes M. P. S., Foureaux G., Joviano-Santos J. V., Nogueira J. C., Ribeiro F. M., Tapia J. C. and Guatimosim C. (2017). Muscle atrophy is associated with cervical spinal motoneuron loss in BACHD mouse model for Huntington's disease. Eur. J. Neurosci. 45, 785-796. 10.1111/ejn.1351010.1111/ejn.1351027992085van der Burg J. M. M., Björkqvist M. and Brundin P. (2009). Beyond the brain: widespread pathology in Huntington's disease. Lancet Neurol. 8, 765-774. 10.1016/S1474-4422(09)70178-410.1016/S1474-4422(09)70178-419608102Vidinská D., Vochozková P., Šmatlíková P., Ardan T., Klíma J., Juhás S., Juhásová J., Bohuslavová B., Baxa M., Valeková I. et al. (2018). Gradual phenotype development in Huntington disease transgenic minipig model at 24 months of age. Neurodegener. Dis. 18, 107-119. 10.1159/00048859210.1159/00048859229870995Vonsattel J. P. G. and Difiglia M. (1998). Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369-384. 10.1097/00005072-199805000-0000110.1097/00005072-199805000-000019596408Wang W., Scheffler K., Esbensen Y. and Eide L. (2016). Quantification of DNA damage by real-time qPCR. Methods Mol. Biol. 1351, 27-32. 10.1007/978-1-4939-3040-1_310.1007/978-1-4939-3040-1_326530672Zielonka D., Piotrowska I., Marcinkowski J. T. and Mielcarek M. (2014). Skeletal muscle pathology in Huntington's disease. Front. Physiol. 5, 380 10.3389/fphys.2014.0038010.3389/fphys.2014.00380PMC418627925339908