Skeletal muscle in an early manifest transgenic minipig model of Huntington’s disease revealed deterioration of mitochondrial bioenergetics and ultrastructure impairment.

Skeletal muscle in an early manifest transgenic minipig model of Huntington’s disease revealed deterioration of mitochondrial bioenergetics and ultrastructure impairment.

Publication date: Jul 05, 2019

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 during the development of HD in muscle has not yet been carefully investigated. To determine the role of mitochondria in skeletal muscle during the early stages of HD development, we analyzed muscle (q. femoris) from 24, 36, 48 and 66 month-old transgenic minipigs that expressed the N-terminal portion of mutated human huntingtin (TgHD) and age-matched wild-type (WT) siblings.Altered ultrastructure of TgHD muscle tissue and mitochondria, significant impairment of respiratory chain complexes (RCCs) I, II and IV as well as citrate synthase, oligomycin-sensitivity conferring protein (OSCP), and the E2 subunit of PDH (PDHE2), and differential expression of optic atrophy 1 protein (OPA1) and dynamin-related protein 1 (Drp1) were found in the skeletal muscle of TgHD minipigs. Statistical analysis identified several parameters that were dependent only on HD status and that could, therefore, be used as potential biomarkers of disease progression. In particular, the biomarker RCC II subunit SDH30 suggests that similar pathogenic mechanisms underlie disease progression in TgHD minipigs and HD patients. A perturbed biochemical phenotype appeared in TgHD minipigs prior to the development of ultrastructural changes and locomotor impairment beginning 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.

Rodinova, M., Krizova, J., Stufkova, H., Bohuslavova, B., Askeland, G., Dosoudilova, Z., Juhas, S., Juhasova, J., Ellederova, Z., Zeman, J., Eide, L., Motlik, J., and Hansikova, H. Skeletal muscle in an early manifest transgenic minipig model of Huntington’s disease revealed deterioration of mitochondrial bioenergetics and ultrastructure impairment. 06562. 2019 Dis Model Mech.

Concepts Keywords
Atrophy DNM1L
Biochemical Mitochondrion
Bioenergetics Histology
Biomarker Branches of biology
Biomarkers Skeletal muscle
Concordance Anatomy
Depression Energetic depression
Differential HD Mitochondrial dysfunction
Dynamin PDH
Etiology
Huntingtin
Huntington
Locomotor
Mitochondria
Mitochondrial
Muscle
N Terminal
Optic Atrophy
Pathogenic
PDH
Phenotype
Respiratory Chain
Skeletal Muscle
Transgenic
Ultrastructural
Ultrastructure
Wild Type

Semantics

Type Source Name
gene UNIPROT MED12
gene UNIPROT OPA1
gene UNIPROT DNM1L
gene UNIPROT DAPK2
gene UNIPROT DENR
gene UNIPROT CRMP1
gene UNIPROT UTRN
disease MESH disease progression
disease DOID RCC
gene UNIPROT XRCC1
disease MESH depression
gene UNIPROT LARGE1
disease MESH optic atrophy 1
gene UNIPROT PDP1
gene UNIPROT ATP5PO
gene UNIPROT ITGBL1
disease MESH development
disease MESH atrophy

Original Article

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