Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice

Gaur, Vidhi; Connor, Timothy; Venardos, Kylie; Henstridge, Darren C.; Martin, Sheree D.; Swinton, Courtney; Morrison, Shona; Aston-Mourney, Kathryn; Gehrig, Stefan M.; Ewijk, Roelof van; Lynch, Gordon S.; Febbraio, Mark A.; Steinberg, Gregory R.; Hargreaves, Mark; Walder, Ken; McGee, Sean L.

doi:10.1111/dom.12896

Cited by 18 publications

(17 citation statements)

References 38 publications

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“…However, this disruption could be caused by the early and long treatment period used, which included gastrulation (5-72 hpf ). HC toxin and scriptaid have recently been shown to enhance glucose uptake and metabolism in mouse skeletal muscle (Tan et al, 2015;Gaur et al, 2017). However, these studies only focused on mechanisms downstream of insulin.…”

Section: Discussionmentioning

confidence: 99%

A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development

et al. 2019

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An early step in pancreas development is marked by the expression of the transcription factor Pdx1 within the pancreatic endoderm, where it is required for the specification of all endocrine cell types. Subsequently, Pdx1 expression becomes restricted to the β-cell lineage, where it plays a central role in β-cell function. This pivotal role of Pdx1 at various stages of pancreas development makes it an attractive target to enhance pancreatic β-cell differentiation and increase β-cell function. In this study, we used a newly generated zebrafish reporter to screen over 8000 small molecules for modulators of pdx1 expression. We found four hit compounds and validated their efficacy at different stages of pancreas development. Notably, valproic acid treatment increased pancreatic endoderm formation, while inhibition of TGFβ signaling led to α-cell to β-cell transdifferentiation. HC toxin, another HDAC inhibitor, enhances β-cell function in primary mouse and human islets. Thus, using a whole organism screening strategy, this study identified new pdx1 expression modulators that can be used to influence different steps in pancreas and β-cell development.

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Section: Discussionmentioning

confidence: 99%

A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development

et al. 2019

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“…Obesity-induced decreases in adiponectin led to decreased insulin sensitivity, but increased circulating insulin levels (Kadowaki et al, 2006;Gaur et al, 2017). Increased insulin levels inhibit AMPK activity in muscle and thereby slow fibre type expression (Valentine et al, 2014).…”

Section: Consequences Of Obesity-induced Decreases In Adiponectin Andmentioning

confidence: 99%

The effects of obesity on skeletal muscle contractile function

Tallis

James

Seebacher

2018

Journal of Experimental Biology

155

146

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Obesity can cause a decline in contractile function of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. We reviewed the literature to establish the current state-of-knowledge of how obesity affects skeletal muscle contraction and relaxation. At a cellular level, the dominant effects of obesity are disrupted calcium signalling and 5'-adenosine monophosphate-activated protein kinase (AMPK) activity. As a result, there is a shift from slow to fast muscle fibre types. Decreased AMPK activity promotes the class II histone deacetylase (HDAC)-mediated inhibition of the myocyte enhancer factor 2 (MEF2). MEF2 promotes slow fibre type expression, and its activity is stimulated by the calcium-dependent phosphatase calcineurin. Obesity-induced attenuation of calcium signalling via its effects on calcineurin, as well as on adiponectin and actinin affects excitation-contraction coupling and excitation-transcription coupling in the myocyte. These molecular changes affect muscle contractile function and phenotype, and thereby and muscle performance. , obesity can increase the absolute force and power produced by increasing the demand on weight-supporting muscle. However, when normalised to body mass, muscle performance of obese individuals is reduced. Isolated muscle preparations show that obesity often leads to a decrease in force produced per muscle cross-sectional area, and power produced per muscle mass. Obesity and ageing have similar physiological consequences. The synergistic effects of obesity and ageing on muscle function may exacerbate morbidity and mortality. Important future research directions include determining: the relationship between time course of weight gain and changes in muscle function; the relative effects of weight gain and high-fat diet feeding per se; the effects of obesity on muscle function during ageing; and if the effects of obesity on muscle function are reversible.

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“…Because previous studies demonstrated that Scriptaid induces muscle-adaptive responses by increasing metabolic genes' expression (14,17), lipid oxidation, and glucose utilization, we sought to examine whether Scriptaid stimulates metabolism in osteocytes. Ocy454-12H cells, a clonal osteocytic cell line, were selected for their high sclerostin expression compared with the original Ocy454 cells.…”

Section: Scriptaid and Pth-regulated Expression Of Metabolic Genes In An Osteocytic Cell Line (Ocy454-12h)mentioning

confidence: 99%

Effects of histone deacetylase inhibitor Scriptaid and parathyroid hormone on osteocyte functions and metabolism

Sun

Uda

Azab

et al. 2019

Journal of Biological Chemistry

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Bone is a highly metabolic organ that undergoes continuous remodeling to maintain its structural integrity. During development, bones, in particular osteoblasts, rely on glucose uptake. However, the role of glucose metabolism in osteocytes is unknown. Osteocytes are terminally differentiated osteoblasts orchestrating bone modeling and remodeling. In these cells, parathyroid hormone (PTH) suppresses Sost/sclerostin expression (a potent inhibitor of bone formation) by promoting nuclear translocation of class IIa histone deacetylase (HDAC) 4 and 5 and the repression of myocyte enhancer factor 2 (MEF2) type C. Recently, Scriptaid, an HDAC complex co-repressor inhibitor, has been shown to induce MEF2 activation and exercise-like adaptation in mice. In muscles, Scriptaid disrupts the HDAC4/5 co-repressor complex, increases MEF2C function, and promotes cell respiration. We hypothesized that Scriptaid, by affecting HDAC4/5 localization and MEF2C activation, might affect osteocyte functions. Treatment of the osteocytic Ocy454-12H cells with Scriptaid increased metabolic gene expression, cell respiration, and glucose uptake. Similar effects were also seen upon treatment with PTH, suggesting that both Scriptaid and PTH can promote osteocyte metabolism. Similar to PTH, Scriptaid potently suppressed Sost expression. Silencing of HDAC5 in Ocy454-12H cells abolished Sost suppression but not glucose transporter type 4 (Glut4) up-regulation induced by Scriptaid. These results demonstrate that Scriptaid increases osteocyte respiration and glucose uptake by mechanisms independent of HDAC complex inhibition. In osteocytes, Scriptaid, similar to PTH, increases binding of HDAC5 to Mef2c with suppression of Sost but only partially increases receptor activator of NF-κB ligand (Rankl) expression, suggesting a potential bone anabolic effect.

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Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice

Cited by 18 publications

References 38 publications

A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development

A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development

The effects of obesity on skeletal muscle contractile function

Effects of histone deacetylase inhibitor Scriptaid and parathyroid hormone on osteocyte functions and metabolism

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