Rosiglitazone Ameliorates Cardiac and Skeletal Muscle Dysfunction by Correction of Energetics in Huntington’s Disease

Abstract

Huntington’s disease (HD) is a rare neurodegenerative disease that is accompanied by skeletal muscle atrophy and cardiomyopathy. Tissues affected by HD (central nervous system [CNS], skeletal muscle, and heart) are known to suffer from deteriorated cellular energy metabolism that manifests already at presymptomatic stages. This work aimed to test the effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist—rosiglitazone on grip strength and heart function in an experimental HD model—on R6/1 mice and to address the mechanisms. We noted that rosiglitazone treatment lead to improvement of R6/1 mice grip strength and cardiac mechanical function. It was accompanied by an enhancement of the total adenine nucleotides pool, increased glucose oxidation, changes in mitochondrial number (indicated as increased citric synthase activity), and reduction in mitochondrial complex I activity. These metabolic changes were supported by increased total antioxidant status in HD mice injected with rosiglitazone. Correction of energy deficits with rosiglitazone was further indicated by decreased accumulation of nucleotide catabolites in HD mice serum. Thus, rosiglitazone treatment may not only delay neurodegeneration but also may ameliorate cardio- and myopathy linked to HD by improvement of cellular energetics.

Prospects of antidiabetic drugs in the treatment of neurodegenerative disease

“…[35,184] Similarly, synthetic agonists belonging to the TZD family and pioglitazone have shown neuroprotective effects in many PD and AD animal models. [91][92][93][94][95][96][97][98] These findings suggest that these antidiabetic drugs may provide new treatment options for patients with NDs. Regarding NDs such as AD, PD, HD, and ALS, antidiabetic drugs such as GLP-1R agonists and PPARγ modulators have shown promise due to their ability to target common pathological pathways, including inflammation and oxidative stress, offering a unified therapeutic strategy.…”

“…[91][92][93][94] TZD and rosiglitazone improve motor deterioration and mutant Htt aggregation in the R6/2 and N171-82Q mouse models of HD. [95][96][97][98] Pioglitazone delays the onset of ALS and significantly enhances the survival time of superoxide dismutase (SOD1)-G93A transgenic ALS mouse model. [99,100] In addition, pioglitazone exhibits neuroprotective effects and mitigates locomotor dysfunction in TDP-43 and FUS Drosophila models of ALS.…”

PPARs and Their Neuroprotective Effects in Parkinson’s Disease: A Novel Therapeutic Approach in α-Synucleinopathy?

“…Therefore, the treatment of neurodegenerative diseases should be considered in light of the multiconvergent theory [ 136 , 137 ] in the face of various neuropathological events such as neuroinflammation, oxidative stress, and protein misfolding. In this context, PPAR analogs would be useful for the treatment of these neurodegenerative disorders [ 138 , 139 , 140 , 141 , 142 ]. For example, PPARγ agonists have been reported to modulate the expression of various AD-related genes, such as Bcl-2, which is involved in hippocampal neurodegeneration [ 143 ], and they have also been shown to reduce Aβ peptide levels both by increasing its clearance and by modifying the activity of secretases that are involved in its metabolism [ 144 , 145 ].…”

“…However, HD is characterized by the presence of involuntary choreatic movements, neuropsychiatric symptoms, and cognitive impairment [ 146 , 147 ]. It originates from a mutation in the huntingtin gene (HTT), which specifically causes aggregation of the huntingtin protein in the cortex and caudate/putamen [ 138 ]. Mitochondrial dysfunction is also related to the development of HD pathogenesis, and PPAR alteration plays an important role [ 76 , 148 ].…”

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

“…Another compound whose levels in HD are significantly out of line with the results obtained for the control group is xanthine, whose plasma levels in HD are decreased [ 218 ]. Furthermore, our previous study indicated higher levels of other compounds related to purine and pyrimidine metabolism, hypoxanthine, and uridine in HD patients relative to healthy controls [ 216 , 220 ].…”