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Deterioration of mitochondrial bioenergetics and ultrastructure impairment in skeletal muscle of a transgenic minipig model in the early stages of Huntington's disease
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SYSNO ASEP 0512108 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Deterioration of mitochondrial bioenergetics and ultrastructure impairment in skeletal muscle of a transgenic minipig model in the early stages of Huntington's disease Author(s) Rodinová, M. (CZ)
Křížová, J. (CZ)
Štufková, H. (CZ)
Bohuslavová, Božena (UZFG-Y) ORCID
Askeland, G. (NO)
Dosoudilová, Z. (CZ)
Juhás, Štefan (UZFG-Y) RID, ORCID
Juhásová, Jana (UZFG-Y) RID, ORCID
Ellederová, Zdeňka (UZFG-Y) RID, ORCID
Zeman, J. (CZ)
Eide, L. (NO)
Motlík, Jan (UZFG-Y) RID, ORCID
Hansíková, H. (CZ)Article number dmm038737 Source Title Disease Models & Mechanisms. - : Company of Biologists - ISSN 1754-8403
Roč. 12, č. 7 (2019)Number of pages 11 s. Publication form Online - E Language eng - English Country GB - United Kingdom Keywords Huntington´s disease ; mitochondrial function ; ultrastructure ; HD large animal model Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology R&D Projects LO1609 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) 7F14308 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UZFG-Y - RVO:67985904 UT WOS 000478759400005 DOI 10.1242/dmm.038737 Annotation Skeletal 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. Workplace Institute of Animal Physiology and Genetics Contact Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Year of Publishing 2020 Electronic address https://dmm.biologists.org/content/12/7/dmm038737
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