Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling

Hsu, Austin; Duan, Qiming; McMahon, Sarah; Huang, Yu; Wood, Sarah A.B.; Gray, Nathanael S.; Wang, Biao; Bruneau, Benoit G.; Haldar, Saptarsi M.

doi:10.1172/jci133753

Cited by 39 publications

(40 citation statements)

References 29 publications

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“…SIK1 acts as a key modulator in many physiological processes, including gluconeogenesis, cellular metabolism and growth (Hsu et al, 2020 ; Liu et al, 2020 ). Nixon et al suggested that SIK1 promotes insulin resistance on a high fat diet in skeletal muscle (Nixon et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation

Cai²,

Shen

et al. 2021

Front. Cell. Neurosci.

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Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.

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Section: Discussionmentioning

confidence: 99%

HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation

Cai²,

Shen

et al. 2021

Front. Cell. Neurosci.

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“…The mechanism by which the synaptic function of the SIK1-MT mice shifts to excitatory dominant remains unknown. SIK has been shown to regulate the subcellular localization and the biological activities of the class IIa histone deacetylases (HDAC4/5/7/9) (Berdeaux et al, 2007 ; Abend et al, 2017 ; Hsu et al, 2020 ) and CRTCs 1, 2, and 3 (Koo et al, 2005 ; Jagannath et al, 2013 ; Nixon et al, 2016 ) through the phosphorylation. SIK1-WT was distributed in the nucleus in a punctate pattern, whereas the SIK1-MT was diffused to the cytoplasm ( Figure 1B ).…”

Section: Discussionmentioning

confidence: 99%

Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1

Badawi

Mori

Kurihara

et al. 2021

Front. Mol. Neurosci.

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Six mutations in the salt-inducible kinase 1 (SIK1)-coding gene have been identified in patients with early infantile epileptic encephalopathy (EIEE-30) accompanied by autistic symptoms. Two of the mutations are non-sense mutations that truncate the C-terminal region of SIK1. It has been shown that the C-terminal-truncated form of SIK1 protein affects the subcellular distribution of SIK1 protein, tempting to speculate the relevance to the pathophysiology of the disorders. We generated SIK1-mutant (SIK1-MT) mice recapitulating the C-terminal-truncated mutations using CRISPR/Cas9-mediated genome editing. SIK1-MT protein was distributed in the nucleus and cytoplasm, whereas the distribution of wild-type SIK1 was restricted to the nucleus. We found the disruption of excitatory and inhibitory (E/I) synaptic balance due to an increase in excitatory synaptic transmission and enhancement of neural excitability in the pyramidal neurons in layer 5 of the medial prefrontal cortex in SIK1-MT mice. We also found the increased repetitive behavior and social behavioral deficits in SIK1-MT mice. The risperidone administration attenuated the neural excitability and excitatory synaptic transmission, but the disrupted E/I synaptic balance was unchanged, because it also reduced the inhibitory synaptic transmission. Risperidone also eliminated the repetitive behavior but not social behavioral deficits. These results indicate that risperidone has a role in decreasing neuronal excitability and excitatory synapses, ameliorating repetitive behavior in the SIK1-truncated mice.

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“…Chondrocyte differentiation, 43 osteocyte mechanotransduction 44 Cardiac deficiency HDAC6 Neuronal differentiation 45 Viable, no visible pathology HDAC7 Cardiac remodelling, 46 neuroprotection, 47 endochondral ossification 48 Embryonic lethality due to dilatation and rupture of blood vessels HDAC9 Cardiac gene expression, 49 vascular calcification 50 Cardiac deficiency HDAC10 Immunoregulation 51 Viable Class 4 HDAC11 Immunoregulation, 52 muscle metabolism, 53 myoblast differentiation 54 Viable pharmacophore layout in these classes is comprised of the metalbinder moiety, the linker and the surface recognition domain 71 ; the surface recognition domain is further subdivided into a polar connecting unit and a hydrophobic cap. 72 This layout was originally proposed based on the X-ray crystallographic studies of an HDAC1 homologue HDLP with suberoylhydroxamic acid (SAHA) and TSA.…”

Section: Hdac5mentioning

confidence: 99%

Recent developments of HDAC inhibitors: Emerging indications and novel molecules

Bondarev

Attwood

Jönsson

et al. 2021

Brit J Clinical Pharma

250

127

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The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC‐inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non‐oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA‐approved agents; however, it often results in increased treatment‐related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.

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Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling

Cited by 39 publications

References 29 publications

HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation

HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation

Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1

Recent developments of HDAC inhibitors: Emerging indications and novel molecules

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