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

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

Research output: Contribution to journalArticle

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Abstract

Background: Presently, there is no effective treatment for the lethal muscle wasting disease Duchenne muscular dystrophy (DMD). Here we show that increased sphingosine-1-phoshate (S1P) through direct injection or via the administration of the small molecule 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, has beneficial effects in acutely injured dystrophic muscles of mdx mice.Methods: We treated mdx mice with and without acute injury and characterized the histopathological and functional effects of increasing S1P levels. We also tested exogenous and direct administration of S1P on mdx muscles to examine the molecular pathways under which S1P promotes regeneration in dystrophic muscles.Results: Short-term treatment with THI significantly increased muscle fiber size and extensor digitorum longus (EDL) muscle specific force in acutely injured mdx limb muscles. In addition, the accumulation of fibrosis and fat deposition, hallmarks of DMD pathology and impaired muscle regeneration, were lower in the injured muscles of THI-treated mdx mice. Furthermore, increased muscle force was observed in uninjured EDL muscles with a longer-term treatment of THI. Such regenerative effects were linked to the response of myogenic cells, since intramuscular injection of S1P increased the number of Myf5nlacz/+ positive myogenic cells and newly regenerated myofibers in injured mdx muscles. Intramuscular injection of biotinylated-S1P localized to muscle fibers, including newly regenerated fibers, which also stained positive for S1P receptor 1 (S1PR1). Importantly, plasma membrane and perinuclear localization of phosphorylated S1PR1 was observed in regenerating muscle fibers of mdx muscles. Intramuscular increases of S1P levels, S1PR1 and phosphorylated ribosomal protein S6 (P-rpS6), and elevated EDL muscle specific force, suggest S1P promoted the upregulation of anabolic pathways that mediate skeletal muscle mass and function.Conclusions: These data show that S1P is beneficial for muscle regeneration and functional gain in dystrophic mice, and that THI, or other pharmacological agents that raise S1P levels systemically, may be developed into an effective treatment for improving muscle function and reducing the pathology of DMD.

Original languageEnglish (US)
Article number20
JournalSkeletal Muscle
Volume3
Issue number1
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

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Inbred mdx Mouse
Regeneration
Sphingosine
Muscles
Duchenne Muscular Dystrophy
Lysosphingolipid Receptors
sphingosine 1-phosphate
Intramuscular Injections
Ribosomal Protein S6
Pathology
Wasting Syndrome

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Orthopedics and Sports Medicine

Cite this

Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice. / Ieronimakis, Nicholas; Pantoja, Mario; Hays, Aislinn L.; Dosey, Timothy L.; Qi, Junlin; Fischer, Karin A.; Hoofnagle, Andrew N.; Sadilek, Martin; Chamberlain, Jeffrey S.; Ruohola-Baker, Hannele; Reyes Gil, Morayma.

In: Skeletal Muscle, Vol. 3, No. 1, 20, 01.08.2013.

Research output: Contribution to journalArticle

Ieronimakis, N, Pantoja, M, Hays, AL, Dosey, TL, Qi, J, Fischer, KA, Hoofnagle, AN, Sadilek, M, Chamberlain, JS, Ruohola-Baker, H & Reyes Gil, M 2013, 'Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice', Skeletal Muscle, vol. 3, no. 1, 20. https://doi.org/10.1186/2044-5040-3-20
Ieronimakis, Nicholas ; Pantoja, Mario ; Hays, Aislinn L. ; Dosey, Timothy L. ; Qi, Junlin ; Fischer, Karin A. ; Hoofnagle, Andrew N. ; Sadilek, Martin ; Chamberlain, Jeffrey S. ; Ruohola-Baker, Hannele ; Reyes Gil, Morayma. / Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice. In: Skeletal Muscle. 2013 ; Vol. 3, No. 1.
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AU - Qi, Junlin

AU - Fischer, Karin A.

AU - Hoofnagle, Andrew N.

AU - Sadilek, Martin

AU - Chamberlain, Jeffrey S.

AU - Ruohola-Baker, Hannele

AU - Reyes Gil, Morayma

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N2 - Background: Presently, there is no effective treatment for the lethal muscle wasting disease Duchenne muscular dystrophy (DMD). Here we show that increased sphingosine-1-phoshate (S1P) through direct injection or via the administration of the small molecule 2-acetyl-4(5)-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, has beneficial effects in acutely injured dystrophic muscles of mdx mice.Methods: We treated mdx mice with and without acute injury and characterized the histopathological and functional effects of increasing S1P levels. We also tested exogenous and direct administration of S1P on mdx muscles to examine the molecular pathways under which S1P promotes regeneration in dystrophic muscles.Results: Short-term treatment with THI significantly increased muscle fiber size and extensor digitorum longus (EDL) muscle specific force in acutely injured mdx limb muscles. In addition, the accumulation of fibrosis and fat deposition, hallmarks of DMD pathology and impaired muscle regeneration, were lower in the injured muscles of THI-treated mdx mice. Furthermore, increased muscle force was observed in uninjured EDL muscles with a longer-term treatment of THI. Such regenerative effects were linked to the response of myogenic cells, since intramuscular injection of S1P increased the number of Myf5nlacz/+ positive myogenic cells and newly regenerated myofibers in injured mdx muscles. Intramuscular injection of biotinylated-S1P localized to muscle fibers, including newly regenerated fibers, which also stained positive for S1P receptor 1 (S1PR1). Importantly, plasma membrane and perinuclear localization of phosphorylated S1PR1 was observed in regenerating muscle fibers of mdx muscles. Intramuscular increases of S1P levels, S1PR1 and phosphorylated ribosomal protein S6 (P-rpS6), and elevated EDL muscle specific force, suggest S1P promoted the upregulation of anabolic pathways that mediate skeletal muscle mass and function.Conclusions: These data show that S1P is beneficial for muscle regeneration and functional gain in dystrophic mice, and that THI, or other pharmacological agents that raise S1P levels systemically, may be developed into an effective treatment for improving muscle function and reducing the pathology of DMD.

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