Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

Ciammola, Andrea; Sassone, Jenny; Alberti, Luisella; Meola, G.; Mancinelli, E.; Russo, Matteo Antonio; Squitieri, Ferdinando; Silani, Vincenzo

doi:10.1038/sj.cdd.4401967

Cited by 83 publications

(81 citation statements)

References 41 publications

(48 reference statements)

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“…In a recent publication referring to human primary muscle cultures from Huntington disease (HD) patients, similar vacuoles were described in HD cultures but not in controls. 17 As in our cultures, these structures were not visible in myotubes. We suggest that this phenomenon is not an in vitro manifestation of HIBM pathological processes, but a possible characteristic of the normal growth of cultured adult skeletal muscle cells.…”

Section: Discussionsupporting

confidence: 51%

“…The changes in apoptotic processes seen in HIBM satellite cells might be one of the initial pathologic events leading to the degeneration of muscle tissue, since they appear during the mitotic phase, while other biological functions of the cells -morphology, proliferation, senescence and differentiation -seem normal. In contrast, in highly degenerative diseases such as HD, CMD and DMD, most basic biological functions are impaired from the early stages of satellite cells activation, 17,19,21 and therefore even when apoptotic processes are involved, it is difficult to point to the initial steps of the process. Presently, the upstream events in HIBM pathophysiology, in terms of intracellular and intercellular signaling, have not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events

et al. 2007

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Hereditary inclusion body myopathy (HIBM) is a unique muscular disorder caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. GNE encodes a bi-functional enzyme acting in the biosynthetic pathway of sialic acid. Since the underlying myopathological mechanism leading to the disease phenotype is poorly understood, we have established human myoblasts cultures, derived from HIBM satellite cells carrying the homozygous M712T mutation, and identified cellular and molecular characteristics of these cells. HIBM and control myoblasts showed similar heterogeneous patterns of proliferation and differentiation. Upon apoptosis induction, phosphatidylserine externalization was similar in HIBM and controls. In contrast, the active forms of caspase-3 and -9 were strongly enhanced in most HIBM cultures compared to controls, while pAkt, downregulated in controls, remained high in HIBM cells. These results could indicate impaired apoptotic signaling in HIBM cells. Since satellite cells enable partial regeneration of the post-mitotic muscle tissue, these altered processes could contribute to the muscle mass loss seen in patients. The identification of survival defects in HIBM affected muscle cells could disclose new functions for GNE in muscle cells.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events

et al. 2007

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“…HD subjects also showed a deficit in mitochondrial oxidative metabolism in skeletal muscles, as judged by a significant decrease in phosphocreatine recovery after exercise [40]. Additionally, in vitro muscle cell cultures exhibited abnormalities in mitochondrial membrane potential and cytochrome 3 release [41].…”

Section: Discussionmentioning

confidence: 99%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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...

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“…In peripheral tissues, mutant huntingtin was reported to affect the activity of mitochondrial complex I (Arenas et al, 1998) and complexes II-III (Ciammola et al, 2006;Turner et al, 2007) along with mitochondrial depolarization, cytochrome c release and increased caspases activity (Ciammola et al, 2006;Turner et al, 2007) in skeletal muscle. In platelets from HD patients, some authors found a decrease in complex I activity (Parker et al, 1990), whereas others reported no changes in the activity of mitochondrial complexes (Gu et al, 1996;Powers et al, 2007a).…”

Section: Introductionmentioning

confidence: 99%

Bioenergetic dysfunction in Huntington's disease human cybrids

Ferreira¹,

Cunha‐Oliveira²,

Nascimento³

et al. 2011

Experimental Neurology

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In this work we studied the mitochondrial-associated metabolic pathways in Huntington's disease (HD) versus control (CTR) cybrids, a cell model in which the contribution of mitochondrial defects from patients is isolated. HD cybrids exhibited an interesting increase in ATP levels, when compared to CTR cybrids. Concomitantly, we observed increased glycolytic rate in HD cybrids, as revealed by increased lactate/pyruvate ratio, which was reverted after inhibition of glycolysis. A decrease in glucose-6-phosphate dehydrogenase activity in HD cybrids further indicated decreased rate of the pentose-phosphate pathway. ATP levels of HD cybrids were significantly decreased under glycolysis inhibition, which was accompanied by a decrease in phosphocreatine. Nevertheless, pyruvate supplementation could not recover HD cybrids' ATP or phosphocreatine levels, suggesting a dysfunction in mitochondrial use of that substrate. Oligomycin also caused a decrease in ATP levels, suggesting a partial support of ATP generation by the mitochondria. Nevertheless, mitochondrial NADH/NAD t levels were decreased in HD cybrids, which was correlated with a decrease in pyruvate dehydrogenase activity and protein expression, suggesting decreased tricarboxylic acid cycle (TCA) input from glycolysis. Interestingly, the activity of alpha-ketoglutarate dehydrogenase, a critical enzyme complex that links the TCA to amino acid synthesis and degradation, was increased in HD cybrids. In accordance, mitochondrial levels of glutamate were increased and alanine was decreased, whereas aspartate and glutamine levels were unchanged in HD cybrids. Conversely, malate dehydrogenase activity from total cell extracts was unchanged in HD cybrids. Our results suggest that inherent dysfunction of mitochondria from HD patients affects cellular bioenergetics in an otherwise functional nuclear background.

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Increased apoptosis, huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects

Cited by 83 publications

References 41 publications

Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events

Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Bioenergetic dysfunction in Huntington's disease human cybrids

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