Transcriptional Signature of an Altered Purine Metabolism in the Skeletal Muscle of a Huntington's Disease Mouse Model.

Michal Mielcarek,Ryszard T Smolenski,Mark Isalan

doi:10.3389/fphys.2017.00127

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disorder, caused by a polyglutamine expansion in the huntingtin protein (HTT). HD has a peripheral component to its pathology: skeletal muscles are severely affected, leading to atrophy, and malfunction in both pre-clinical and clinical settings. We previously used two symptomatic HD mouse models to demonstrate the impairment of the contractile characteristics of the hind limb muscles, which was accompanied by a significant loss of function of motor units. The mice displayed a significant reduction in muscle force, likely because of deteriorations in energy metabolism, decreased oxidation, and altered purine metabolism. There is growing evidence suggesting that HD-related skeletal muscle malfunction might be partially or completely independent of CNS degeneration. The pathology might arise from mutant HTT within muscle (loss or gain of function). Hence, it is vital to identify novel peripheral biomarkers that will reflect HD skeletal muscle atrophy. These will be important for upcoming clinical trials that may target HD peripherally. In order to identify potential biomarkers that might reflect muscle metabolic changes, we used qPCR to validate key gene transcripts in different skeletal muscle types. Consequently, we report a number of transcript alterations that are linked to HD muscle pathology.

Highlights

Skeletal muscle loss and dysfunction are often associated with aging but are found in many chronic diseases with diverse etiologies (Vinciguerra et al, 2010)
Since we previously showed that purine metabolism is significantly altered in pre-clinical Huntington’s disease (HD) settings (Mielcarek et al, 2015), our current study exclusively focused on the key transcriptional elements of this process as these might serve as important molecular biomarkers for up-coming pre-clinical and clinical studies in HD
In order to establish the transcriptional signature related to the pathology observed in HD skeletal muscle, we employed the R6/2 transgenic mouse model of HD, representing the fully symptomatic stage of a rapid-onset form of the disease

Summary

Introduction

Skeletal muscle loss and dysfunction are often associated with aging but are found in many chronic diseases with diverse etiologies (Vinciguerra et al, 2010). The list includes Huntington’s disease (HD), which is a monogenic neurodegenerative disorder caused by a CAG-repeat expansion within the huntingtin gene (HTT). The best functional description of HTT is as a “scaffolding protein.”. This is because HTT has many interaction partners and these are involved in a wide variety of cellular processes, including gene transcription, intracellular signaling, trafficking, endocytosis, and metabolism (Harjes and Wanker, 2003), one might describe HD as a multi-system disorder (Mielcarek, 2015). The best functional description of HTT is as a “scaffolding protein.” This is because HTT has many interaction partners and these are involved in a wide variety of cellular processes, including gene transcription, intracellular signaling, trafficking, endocytosis, and metabolism (Harjes and Wanker, 2003), one might describe HD as a multi-system disorder (Mielcarek, 2015).

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Methods

Results