Deterioration of mitochondrial bioenergetics and ultrastructure impairment in skeletal muscle of a transgenic minipig model in the early stages of Huntington's disease
| العنوان: | 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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| المؤلفون: | Rodinova, Marie, Krizova, Jana, Stufkova, Hana, Bohuslavova, Bozena, Askeland, Georgina, Dosoudilova, Zaneta, Juhas, Stefan, Juhasova, Jana, Ellederova, Zdenka, Zeman, Jiri, Eide, Lars, Motlik, Jan, Hansikova, Hana |
| المصدر: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 12, Iss 7 (2019) |
| بيانات النشر: | The Company of Biologists Ltd., 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Swine, lcsh:Medicine, Skeletal muscle, Oxidative Phosphorylation, Animals, Genetically Modified, Electron Transport, Mitochondrial Proteins, HD large animal model, lcsh:Pathology, Animals, Humans, Disease development, Muscle, Skeletal, Huntingtin Protein, lcsh:R, Body Weight, Huntington's disease, DNA, Mitochondria, Muscle, Disease Models, Animal, Huntington Disease, Ultrastructure, Mutation, Disease Progression, Swine, Miniature, Mitochondrial function, Energy Metabolism, Biomarkers, lcsh:RB1-214, Research Article |
| الوصف: | 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. This article has an associated First Person interview with the first author of the paper. Summary: Specific mitochondrial parameters in muscle of a minipig model of Huntington's disease can be used as potential biomarkers of disease progression and suggest that similar pathogenic mechanisms underlie disease progression in TgHD minipigs and HD patients. |
| تدمد: | 1754-8403 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::547e46f6e86b21514372cae787de17dcTest http://hdl.handle.net/10852/75794Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.pmid.dedup....547e46f6e86b21514372cae787de17dc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17548403 |
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