Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice

Ieronimakis, Nicholas; Pantoja, Mario; Hays, Aislinn; Dosey, Timothy L.; Qi, Junlin; Fischer, Karin A.; Hoofnagle, Andrew N.; Sadı́lek, Martin; Chamberlain, Jeffrey S.; Ruohola‐Baker, Hannele; Reyes, Morayma

doi:10.1186/2044-5040-3-20

Cited by 52 publications

(81 citation statements)

References 76 publications

(103 reference statements)

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“…In dystrophic mice, treatment with THI after muscle injury has beneficial muscle effects, enhancing satellite-cell-based regeneration as well as significantly increasing muscle fiber size and specific force (Loh et al, 2012; Ieronimakis et al, 2013). In addition, the hallmarks of DMD pathology, fibrosis and fat deposition, are also reduced in THI-treated mdx mice.…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy

Nguyen-Tran

Hait

Sperber

et al. 2013

Disease Models &Amp; Mechanisms

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Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease. Studies in Drosophila showed that genetic increase of the levels of the bioactive sphingolipid sphingosine-1-phosphate (S1P) or delivery of 2-acetyl-5-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, suppresses dystrophic muscle degeneration. In the dystrophic mouse (mdx), upregulation of S1P by THI increases regeneration and muscle force. S1P can act as a ligand for S1P receptors and as a histone deacetylase (HDAC) inhibitor. Because Drosophila has no identified S1P receptors and DMD correlates with increased HDAC2 levels, we tested whether S1P action in muscle involves HDAC inhibition. Here we show that beneficial effects of THI treatment in mdx mice correlate with significantly increased nuclear S1P, decreased HDAC activity and increased acetylation of specific histone residues. Importantly, the HDAC2 target microRNA genes miR-29 and miR-1 are significantly upregulated, correlating with the downregulation of the miR-29 target Col1a1 in the diaphragm of THI-treated mdx mice. Further gene expression analysis revealed a significant THI-dependent decrease in inflammatory genes and increase in metabolic genes. Accordingly, S1P levels and functional mitochondrial activity are increased after THI treatment of differentiating C2C12 cells. S1P increases the capacity of the muscle cell to use fatty acids as an energy source, suggesting that THI treatment could be beneficial for the maintenance of energy metabolism in mdx muscles.

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Section: Resultsmentioning

confidence: 99%

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy

Nguyen-Tran

Hait

Sperber

et al. 2013

Disease Models &Amp; Mechanisms

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“…In support of this possibility, elevation of the S1P level by inhibiting SPL activity has been demonstrated to improve regeneration of pancreas [90] and skeletal muscles [91]. …”

Section: Novel Potential Approaches To Enhancing the Responsivenesmentioning

confidence: 99%

The role of sphingosine-1 phosphate and ceramide-1 phosphate in trafficking of normal stem cells and cancer cells

Ratajczak

Suszyńska

Borkowska

et al. 2013

Expert Opinion on Therapeutic Targets

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Introduction A common feature of many types of cells is their responsiveness to chemotactic gradients of factors for which they express the corresponding receptors. The most studied chemoattractants so far are peptide-based growth factors and a family of cytokines endowed with strong chemotactic properties, called chemokines. However, additional evidence has accumulated that, in addition to these peptide-based chemoattractants, an important role in cell migration is played by bioactive lipids. Areas covered Solid evidence has accumulated that two bioactive phosphorylated sphingolipids that are derivatives of sphingolipid metabolism, namely sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), are potent chemoattractants for a variety of cells. In this review, we will discuss the effect of these two phosphorylated sphingolipids on the trafficking of normal and malignant cells, and, in particular, we will focus on their role in trafficking of normal hematopoietic stem/progenitor cells. Unlike other mediators, S1P under steady state conditions maintain a steep gradient between interstitial fluid and peripheral blood and lymph across the endothelial barrier, which is important in the egress of cells from bone marrow. Both S1P and C1P may be upregulated in damaged tissues, which may result in reversal of this gradient. Expert opinion S1P and C1P are important regulators of the trafficking of normal and malignant cells, and modification of their biological effects will have important applications in optimizing stem cell mobilization and homing, tissue organ/regeneration, and preventing cancer metastasis.

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“…In the case of THI, this has been done by us and others 10 , 11 . It will be important now to extend this work to THI-oxime and FTY720.…”

Section: Drosophila As a Tool For The Discovery Of Small Molecule Thementioning

confidence: 85%

“…So far we 10 and others 11 have undertaken studies with a more therapeutic slant by analyzing small molecules that elevate S1P levels in mdx mice (Fig. 1C).…”

Section: Elevation Of S1p Promotes the Reduction Of Pathological Sympmentioning

confidence: 99%

“…More specifically, we have found that delivery of S1P itself into dystrophic muscle increases muscle progenitor cell proliferation; and have also found that systemic delivery of a putative S1P lyase inhibitor, 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), dramatically reduces fibrosis and fat deposition in dystrophic mice as well as improves the function of acutely injured dystrophic muscle 10 . Furthermore, we have recently shown that THI can also promote a functional benefit to uninjured dystrophic muscle in a one month long treatment using young mdx mice 10 . It is also interesting to note that THI is a trace component of Caramel Color III, which is categorized by the FDA as GRAS (generally recognized as safe) making it an interesting candidate for possible use in humans.…”

Section: Elevation Of S1p Promotes the Reduction Of Pathological Sympmentioning

confidence: 99%

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Drosophilaas a starting point for developing therapeutics for the rare disease Duchenne Muscular Dystrophy

Pantoja¹,

Ruohola‐Baker

2013

Rare Diseases

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Progress into developing therapeutics for rare diseases can be accelerated for those diseases that can be modeled in genetically tractable organisms. Here we comment on one disease, Duchenne Muscular Dystrophy (DMD), modeled in Drosophila that brought together disparate lines of research toward the goal of developing a therapeutic. Though the bioactive lipid sphingosine 1-phosphate (S1P) has been implicated in many anabolic processes in many cell types and tissues, including muscle, this work confirmed the therapeutic potential of assessing this pathway for DMD. Genetic dissection of sphingolipid metabolism showed the suppression of muscle structural and functional defects in flies. Moreover, improvement of muscle defects using known pharmacological agents that raise S1P levels in vivo highlight the potential of Drosophila as a drug-screening tool for DMD. We and others have extended S1P studies into the mouse model of DMD and have shown a partial amelioration of symptoms associated with DMD. Translation of this work to mammals makes the sphingolipid metabolism pathway a promising target for further drug development that may benefit the human condition.

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Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice

Cited by 52 publications

References 76 publications

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy

The role of sphingosine-1 phosphate and ceramide-1 phosphate in trafficking of normal stem cells and cancer cells

Drosophilaas a starting point for developing therapeutics for the rare disease Duchenne Muscular Dystrophy

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