BackgroundHuntington's disease (HD) is a fatal inherited neurodegenerative disease, caused by a

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments.

For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes.

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Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

Religiosity has been related to psychological wellbeing outcomes. Although this relationship is primarily based on studies of church attendance or prayer and wellbeing, more recent work has focused on the potential mechanisms that may mediate the religion-wellbeing findings. One of the major function of religion is finding of meaning of life and improving hope. Recent studies have indicated that hope and meaning of life are the potential variables mediate between religion and wellbeing. It was hypothesized that one pathway through which religiosity may exert its positive influence on psychological wellbeing is through finding meaning of life and improving hope. One study was conducted examining the relationships among spiritual experiences, hope, meaning of life and psychological wellbeing operationalized as satisfaction with life, positive affect and negative affect. The following research tools were used: Daily Spiritual Experiences Scale, Purpose in Life Test, Hearth Hope Index, Cantril Ladder, Positive and Negative Affect Schedule. Meaning of life and hope were noticed to mediate between spiritual experiences and satisfaction with life as well as between spiritual experiences and positive affect. Spiritual experiences were not related to negative affect. Both meaning of life and hope predicted negative affect. This study found meaning of life and hope to be an important factors in the religion-wellbeing relationship and related to positive psychological outcomes, including improved satisfaction with life and positive affect as well as reduced negative affect.

The authors investigated the relationship of purpose of life, and hope in the happiness and life satisfaction of patients with cancer during or following cancer treatment. Fifty cancer patients were interviewed during recovery in two Warsaw medical centers. The primary measures used were Purpose in Life Test, Herth Hope Index, Happiness and Social Well-Being tools by Czapiński, and the Cantril Ladder of Satisfaction with Life, as well as medical and demographic measures. Purpose in life was correlated with measures of happiness, and satisfaction with life. Hope was correlated with current happiness, and four measures of satisfaction with life. Patients who had cancer longer, that is, duration of disease, showed lower scores for purpose in life, and number of friends. The longer the time of cancer treatment, the lower were patients' scores for desire for life. Purpose in life and hope were positively correlated with eleven measures of happiness and satisfaction in life. The cancer variables negatively correlated with loss of friends and six variables of happiness, and satisfaction in life, suggesting the impact that having cancer treatment had on patients' lives. Psychological support in the cancer center was helpful to patients in and out of treatment.

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