Evidences for Mutant Huntingtin Inducing Musculoskeletal and Brain Growth Impairments via Disturbing Testosterone Biosynthesis in Male Huntington Disease Animals

Abstract

Body weight (BW) loss and reduced body mass index (BMI) are the most common peripheral alterations in Huntington disease (HD) and have been found in HD mutation carriers and HD animal models before the manifestation of neurological symptoms. This suggests that, at least in the early disease stage, these changes could be due to abnormal tissue growth rather than tissue atrophy. Moreover, BW and BMI are reported to be more affected in males than females in HD animal models and patients. Here, we confirmed sex-dependent growth alterations in the BACHD rat model for HD and investigated the associated contributing factors. Our results showed growth abnormalities along with decreased plasma testosterone and insulin-like growth factor 1 (IGF-1) levels only in males. Moreover, we demonstrated correlations between growth parameters, IGF-1, and testosterone. Our analyses further revealed an aberrant transcription of testosterone biosynthesis-related genes in the testes of BACHD rats with undisturbed luteinizing hormone (LH)/cAMP/PKA signaling, which plays a key role in regulating the transcription process of some of these genes. In line with the findings in BACHD rats, analyses in the R6/2 mouse model of HD showed similar results. Our findings support the view that mutant huntingtin may induce abnormal growth in males via the dysregulation of gene transcription in the testis, which in turn can affect testosterone biosynthesis.

Intravenous MSC-Treatment Improves Impaired Brain Functions in the R6/2 Mouse Model of Huntington’s Disease via Recovered Hepatic Pathological Changes

“…Cytochrome P450s (CYPs) are a big family of proteins predominantly expressed in the liver and are crucial for detoxification besides the metabolic activation of xenobiotics [ 43 ]. Several studies have reported that mHTT causes dysregulated transcription of CYPs in HD patients and animals [ 44 , 45 , 46 , 47 ]. Furthermore, a significant body of research indicates that the reduced activity of CYP enzymes is associated with the severity of chronic liver disease with the exception of an irreversible correlation observed in a few of these enzymes [ 48 , 49 , 50 ].…”

“…Furthermore, reduced CYP46 levels in the plasma [ 83 ] and putamen of HD patients, as well as in the striatum of R6/2 mice [ 46 ], have been previously reported. Our earlier study had also demonstrated a significant lower expression of CYP11A in the testis of BACHD rats [ 44 ]. As HTT functions as a transcription factor [ 84 ], reduced expression levels of HTT in hepatocytes have resulted in altered liver gene expression patterns [ 85 ].…”

“…animals [44][45][46][47]. Furthermore, a significant body of research indicates that the reduced activity of CYP enzymes is associated with the severity of chronic liver disease with the exception of an irreversible correlation observed in a few of these enzymes [48][49][50].…”