Deterioration of mitochondrial bioenergetics and ultrastructure impairment in skeletal muscle of a transgenic minipig model in the early stages of Huntington's disease.

Marie Rodinova,Zdenka Ellederova,Jan Motlik,Georgina Askeland,Lars Eide,Zaneta Dosoudilova,Stefan Juhas,Jiri Zeman,Hana Hansikova,Jana Krizova,Bozena Bohuslavova,Hana Stufkova,Jana Juhasova

doi:10.1242/dmm.038737

Abstract

ABSTRACTSkeletal 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.

Highlights

Huntington’s disease (HD) is neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (Htt) (Vonsattel and DiFiglia, 1998; Novak and Tabrizi, 2010)
Presence of mutated Htt protein (mHtt) in skeletal muscle of the HD model First, we monitored the occurrence of mHtt in skeletal muscle samples from the TgHD animals. mHtt was found in TgHD muscles at all ages examined (Fig. S1)
The large animal model is suitable for extensive investigations on skeletal muscle Skeletal muscle wasting and atrophy are severe clinical impairments that are connected with the progression of HD (Zielonka et al, 2014)

Summary

Introduction

Huntington’s disease (HD) is neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (Htt) (Vonsattel and DiFiglia, 1998; Novak and Tabrizi, 2010). The disease is caused by an expansion that leads to the inclusion of over 35 CAG repeats in exon 1 of the huntingtin gene (HTT), resulting in the production of mutated Htt protein (mHtt) (Kremer et al, 1994). Ubiquitous mHtt expression causes lesions in specific brain areas and acts in peripheral tissues, including skeletal and cardiac muscle, and blood cells (Carroll et al, 2015; Trottier et al, 1995). The weight loss observed in both HD patients and animal models is associated with increased energy expenditure and global muscle wasting that is independent of locomotor activity (van der Burg et al, 2009). Recent evidence indicates that muscle wasting in HD may occur independently of basal ganglia and cortex dysfunction (Mantovani et al, 2016; van der Burg et al, 2009)

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