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

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.

Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy

“…First, AMPD3 is a cytosolic enzyme that mediates the thermodynamically irreversible deamination of AMP to IMP. AMPD3 mRNA is reported to be one of the most upregulated genes in atrophying muscles from cancer [149], diabetes [149], renal failure [150], aging [151], Huntington's disease [152], fasting [149,153], unloading [154], and denervation [153,155,156]. However, AMPD3 expression has not been reported to increase in muscular dystrophy.…”

Neuro-Cardio Mechanisms in Huntington’s Disease and Other Neurodegenerative Disorders

“…One of the most studied peripheral pathologies in HD is skeletal muscle atrophy (reviewed in Zielonka et al, 2014a ; Mielcarek and Isalan, 2015 ; Mielcarek et al, 2015a , 2017 ). In fact, a recent study showed that rescuing skeletal muscle degeneration alone had a profound therapeutic effect in HD model mice.…”

Abnormalities in the Motor Unit of a Fast-Twitch Lower Limb Skeletal Muscle in Huntington’s Disease

“…Previous works from other groups reported changes in NMJs and muscles in R6/2 mouse model for HD that could be related to motoneurons degeneration (Ribchester et al, 2004;Mielcarek and Isalan, 2015;Khedraki et al, 2017). However, these authors did not look at the spinal cords to address whether motoneurons were indeed affected in R6/2 mice.…”

“…Menalled et al, 2009;Yang and Gray, 2011). Experiments performed in these animal models allowed the identification of mutant huntingtin protein (mHTT) not only in the CNS but also in peripheral structures, such as skeletal muscles (van der Burg et al, 2009;Zielonka et al, 2014;Mielcarek et al, 2017). In fact, mouse HD models exhibited pronounced skeletal muscle atrophy, a pathophysiological finding that could be due to accumulation of mHTT in skeletal muscles, motoneurons, or both (Khedraki et al, 2017).…”