Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy

Minamiyama, Makoto; Katsuno, Masahisa; Adachi, Hiroaki; Waza, Masahiro; Sang, Chen; Kobayashi, Yasushi; Tanaka, Fumiaki; Doyu, Manabu; Inukai, Akira; Sobue, Gen

doi:10.1093/hmg/ddh131

Cited by 243 publications

(181 citation statements)

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“…Actually, the therapeutic effect of an HDAC inhibitor was observed only within a narrow range of lower doses, and the effect changed to be toxic at higher doses in polyQ transgenic mice. 35 These results suggest that the use of HDAC inhibitors in polyQ diseases requires careful consideration to avoid causing a lethal degree of Ku70 acetylation. The present study focused on the toxicity of expanded polyQ derived from the causative gene (mutated ataxin3) of MJD.…”

Section: Discussionmentioning

confidence: 98%

“…Based on this hypothesis, the maintenance of histone acetylation by HDAC inhibitors, such as trichostatin A (TSA), has been examined for the reduction of polyQ toxicity. 3,34,35 However, an HDAC inhibitor was recently shown to induce apoptosis in neuroblastoma cells by increasing Ku70 acetylation and promoting Bax-mediated cell death. 14 Therefore, it is plausible that HDAC inhibitors have a 'double-edge' activity in the context of After 48 h, cells were harvested and immunoprecipitation was performed using 6A7 anti-Bax monoclonal antibody polyQ toxicity; they attenuate polyQ toxicity by maintaining histone acetylation in the nucleus, but promote Bax-mediated cell death by acetylating Ku70 in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

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Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Yokota

Gama

et al. 2007

Cell Death Differ

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Polyglutamine (polyQ) diseases, such as Huntington's disease and Machado-Joseph disease (MJD), are caused by gain of toxic function of abnormally expanded polyQ tracts. Here, we show that expanded polyQ of ataxin-3 (Q79C), a gene that causes MJD, stimulates Ku70 acetylation, which in turn dissociates the proapoptotic protein Bax from Ku70, thereby promoting Bax activation and subsequent cell death. The Q79C-induced cell death was significantly blocked by Ku70 or Bax-inhibiting peptides (BIPs) designed from Ku70. Furthermore, expression of SIRT1 deacetylase and the addition of a SIRT1 agonist, resveratrol, reduced Q79C toxicity. In contrast, mimicking acetylation of Ku70 abolished the ability of Ku70 to suppress Q79C toxicity. These results indicate that Bax and Ku70 acetylation play important roles in Q79C-induced cell death, and that BIP may be useful in the development of therapeutics for polyQ diseases. Nine inherited neurodegenerative disorders with expanded polyglutamine (polyQ) are caused by mutations in different genes, but they likely share the common pathology in which expanded polyQ gains toxic functions. 1 The molecular mechanism of neuronal toxicity of polyQ remains enigmatic. Recent findings suggest that the intracellular aggregation of polyQ causes cellular stress responses that trigger neuronal cell death. 1 It is hypothesized that polyQ aggregation suppresses neuronal transcriptional activity by sequestering histone acetyltransferases (HAT) from chromosomes and thus polyQ causes neuronal cell death. [2][3][4] Bax is a proapoptotic member of Bcl-2 family proteins that plays a key role in programmed cell death in neurons. 5,6 Recently, mutant huntingtin with expanded polyQ was shown to activate p53 and increase the expression level of Bax. 7 Based on these previous findings, we became interested in examining the role of Bax in polyQ-induced cell death. Recently, we developed a series of cytoprotective membrane-permeable pentapeptides that rescue cells from Baxmediated cell death. These peptides are named Bax-inhibiting peptides (BIPs) and were designed from the Bax binding domain of Ku70. [8][9][10] Ku70 is a multifunctional protein playing roles in DNA repair and cell survival. 11 Ku70 has been shown to inhibit Bax-mediated cell death by binding Bax in the cytosol. 12-14 The present study demonstrates that BIP can rescue cells from polyQ toxicity, and that polyQ promotes Bax-mediated cell death by inducing Ku70 acetylation that activates Bax. ResultsBIP suppresses Q79C-induced cell death. BIPs consisting of five amino acids (e.g. VPMLK and VPTLK) were used in this study. A mutated peptide (i.e. IPMIK) that does not bind Bax but retains cell permeability was also used in this study as a negative control (NC). For the investigation of polyQ toxicity, we used the C-terminal, truncated fragment of the Machado-Joseph disease 1 (MJD1) gene product, ataxin-3, which includes an expanded polyQ stretch (79 glutamine repeats, Q79C). 15,16 As a negative control, ataxin-3 C-terminus with 22 or 35 glutamine rep...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Yokota

Gama

et al. 2007

Cell Death Differ

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“…Recent in vivo studies have shown that treatment with HDAC inhibitors of a wide range of structures provide neuroprotective effects in models of various motor neuron disorders. [44][45][46][47] However, the roles of glia under therapeutic mechanisms of HDAC inhibitors were not investigated. Here we showed that the neurotrophic effects of VPA, a HDAC inhibitor of short-chain fatty acid structure, were associated with Figure 5 VPA is neuroprotective against LPS-induced DA neurodegeneration in rat primary mesencephalic neuronglia cultures.…”

Section: Discussionmentioning

confidence: 99%

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

et al. 2006

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Valproate (VPA), one of the mood stabilizers and antiepileptic drugs, was recently found to inhibit histone deacetylases (HDAC). Increasing reports demonstrate that VPA has neurotrophic effects in diverse cell types including midbrain dopaminergic (DA) neurons. However, the origin and nature of the mediator of the neurotrophic effects are unclear. We have previously demonstrated that VPA prolongs the survival of midbrain DA neurons in lipopolysaccharide (LPS)-treated neuron-glia cultures through the inhibition of the release of pro-inflammatory factors from microglia. In this study, we report that VPA upregulates the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) from astrocytes and these effects may play a major role in mediating VPA-induced neurotrophic effects on DA neurons. Moreover, VPA pretreatment protects midbrain DA neurons from LPS or 1-methyl-4-phenylpyridinium (MPP þ )-induced neurotoxicity. Our study identifies astrocyte as a novel target for VPA to induce neurotrophic and neuroprotective actions in rat midbrain and shows a potential new role of cellular interactions between DA neurons and astrocytes. The neurotrophic and neuroprotective effects of VPA also suggest a utility of this drug for treating neurodegenerative disorders including Parkinson's disease. Moreover, the neurotrophic effects of VPA may contribute to the therapeutic action of this drug in treating bipolar mood disorder that involves a loss of neurons and glia in discrete brain areas.

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“…In fact, pharmacological inhibitors of HDACs have also shown promise in preclinical models of diseases of muscle, including amyotrophic lateral sclerosis (Yoo & Ko, 2011), spinal muscular atrophy (Minamiyama et al ., 2004) and muscular dystrophy (Consalvi et al ., 2013). For example, HDAC inhibitors reduce fibrosis and improve muscle function in a mouse model of muscular dystrophy (Consalvi et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Walsh¹,

et al. 2015

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SummarySarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.

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Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy

Cited by 243 publications

References 50 publications

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

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