TY - JOUR
T1 - Increased sphingosine-1-phosphate improves muscle regeneration in acutely injured mdx mice
AU - Ieronimakis, Nicholas
AU - Pantoja, Mario
AU - Hays, Aislinn L.
AU - Dosey, Timothy L.
AU - Qi, Junlin
AU - Fischer, Karin A.
AU - Hoofnagle, Andrew N.
AU - Sadilek, Martin
AU - Chamberlain, Jeffrey S.
AU - Ruohola-Baker, Hannele
AU - Reyes, Morayma
N1 - Funding Information:
We thank Zack Usa, Alex Nelson and Jessica Becker for technical help. We thank Dr Guenter Daum for advice and guidance on S1P based approaches. We also thank Dr Guenter Daum and Dr LeBoeuf Renee for sharing Akt-and S1P-related antibodies. We thank Dr Zipora Yablonka-Reuveni for the Myf5nlacZ/+ reporter mice. Finally, we would like to thank Dr Nick Whitehead for his technical guidance on myography. This work was supported by the University of Washington Center for Commercialization (C4C), Departments of Pathology and Laboratory Medicine, University of Washington; Provost Bridge grant to MR; University of Washington Nathan Shock Center of Excellence in the Basic Biology of Aging and the Genetic Approaches to Aging Training Grant T32 AG00057 to NI; and the American Recovery and Reinvestment Act of 2009 (ARRA) Challenge Grant 5RC1AR058520, R01GM083867, R01GM097372 and 1P01GM081619 to HRB. Support was also received from the Washington Research Foundation, the Duchenne Alliance, RaceMD and Ryan’s Quest to NI, MP, MR and HRB.
PY - 2013/8/1
Y1 - 2013/8/1
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.
AB - 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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U2 - 10.1186/2044-5040-3-20
DO - 10.1186/2044-5040-3-20
M3 - Article
C2 - 23915702
AN - SCOPUS:84880886286
SN - 2044-5040
VL - 3
JO - Skeletal Muscle
JF - Skeletal Muscle
IS - 1
M1 - 20
ER -