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Sphingosine-1-phosphate, satellite cells, and Duchenne muscular dystrophy


Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. It is x-linked and primarily affects boys, but is rarely also diagnosed in girls. DMD is characterized by progressive loss of skeletal muscle strength associated with pathological features including pseudohypertrophy of the calf muscles of the leg, muscle necrosis and regeneration, and eventual muscle replacement by adipose tissue (1). The disease affects the heart and skeletal muscles including the diaphragm, and patients usually succumb to the disease in their twenties due to heart and respiratory failure. Mutations in the dystrophin gene are responsible for DMD (2). Dystrophin’s major role is to distribute the forces generated by muscle contraction. Dystrophin mutation leads to muscle degeneration through various mechanisms.

Satellite cells (SCs) represent a population of adult stem cells that are found in skeletal muscle and are responsible for the regenerative capacity of muscle (3). SCs exist in a quiescent state under resting conditions. Disruption of the muscle architecture by traumatic injury or genetic instability results in exposure of SCs to bioactive factors released from injured muscle and its niche, leading to their activation (4) . Activated SCs undergo a burst of proliferation and then migrate from the muscle periphery to sites of injury. SCs fuse with the injured myofiber, thereby stimulating a myogenic program that promotes muscle repair (5). During the early stages of DMD, SC activation and accompanying skeletal muscle regeneration compensate for fiber loss. However, the chronic/degenerative phase of DMD is caused by a failure of regeneration to keep up with ongoing injury and destruction of muscle fibers (6). This may be accounted for in part by an exhaustion of SC reserves, or their proliferative capacity or myogenic potential. It is most likely that SC myogenic potential is compromised by the pathological environment (7-11) . Steroids, which represent the mainstay of therapy in DMD, increase SCs in human muscle (12) . Development of methods that replenish the endogenous SC compartment, allow expansion of donor SCs for cellular therapy, or enhance the myogenic potential of SCs are being explored as therapeutic strategies in DMD (13).  A number of strategies have been shown to improve engraftment of allogeneic SCs, but none have yet been established as effective clinical approaches.

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that acts through S1P receptor (S1PR) activation and other mechanisms to promote cell survival, proliferation and migration (14). S1P induces growth-promoting, inflammatory/immune (15, 16) and other signaling pathways implicated in muscle homeostasis and repair (17-23). S1P regulates myoblast differentiation, is a muscle trophic factor, and activates muscle stem cells or satellite cells through poorly understood mechanisms (24-26). Our published studies demonstrate that tight control over sphingolipid metabolism is critical for muscle homeostasis (27, 28). We have observed that S1P levels, signaling and metabolism change dynamically in response to murine muscle injury. We find that S1P deficiency due to targeted disruption of the major sphingosine kinase (SK) gene Sphk1 impairs muscle regeneration and reduces SC recruitment, proliferation and differentiation. Further, we showed that mdx mice that serve as a model of DMD are in a state of S1P deficiency, and administration of a nontoxic inhibitor of S1P lyase (SPL) called tetrahydroxybutylimidazole (THI) blocks S1P degradation and improves mdx mouse SC recruitment and muscle regeneration. THI and other SPL inhibitors are also known to ameliorate autoimmune diseases by reducing lymphocyte trafficking and invasion into tissues, thereby reducing inflammation. Based on these findings, we hypothesize that boosting S1P signaling by inhibiting SPL may provide a new strategy for improving muscle function and survival in patients with DMD by improving muscle regeneration through SC expansion and by reducing inflammatory muscle destruction.

References

  1. Deconinck, N., and Dan, B. (2007) Pathophysiology of duchenne muscular dystrophy: current hypotheses. Pediatr. Neurol. 36, 1-7
  2. Hoffman, E. P., Brown, R. H., Jr., and Kunkel, L. M. (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51, 919-928
  3. Le Grand, F., and Rudnicki, M. A. (2007) Skeletal muscle satellite cells and adult myogenesis. Curr. Opin. Cell Biol. 19, 628-633
  4. Kastner, S., Elias, M. C., Rivera, A. J., and Yablonka-Reuveni, Z. (2000) Gene expression patterns of the fibroblast growth factors and their receptors during myogenesis of rat satellite cells. J. Histochem. Cytochem. 48, 1079-1096
  5. Zammit, P. S., Partridge, T. A., and Yablonka-Reuveni, Z. (2006) The skeletal muscle satellite cell: the stem cell that came in from the cold. J. Histochem. Cytochem. 54, 1177-1191
  6. Emery, A. E. (2002) The muscular dystrophies. Lancet 359, 687-695
  7. Morgan, J. E., and Zammit, P. S. (2010) Direct effects of the pathogenic mutation on satellite cell function in muscular dystrophy. Exp. Cell Res. 316, 3100-3108
  8. Berg, Z., Beffa, L. R., Cook, D. P., and Cornelison, D. D. (2011) Muscle satellite cells from GRMD dystrophic dogs are not phenotypically distinguishable from wild type satellite cells in ex vivo culture. Neuromuscul. Disord. 21, 282-290
  9. Kottlors, M., and Kirschner, J. (2010) Elevated satellite cell number in Duchenne muscular dystrophy. Cell Tissue Res. 340, 541-548
  10. Alexakis, C., Partridge, T., and Bou-Gharios, G. (2007) Implication of the satellite cell in dystrophic muscle fibrosis: a self-perpetuating mechanism of collagen overproduction. Am J Physiol Cell Physiol 293, C661-669
  11. Schuierer, M. M., Mann, C. J., Bildsoe, H., Huxley, C., and Hughes, S. M. (2005) Analyses of the differentiation potential of satellite cells from myoD-/-, mdx, and PMP22 C22 mice. BMC Musculoskelet Disord 6, 15
  12. Hussein, M. R., Abu-Dief, E. E., Kamel, N. F., and Mostafa, M. G. (2010) Steroid therapy is associated with decreased numbers of dendritic cells and fibroblasts, and increased numbers of satellite cells, in the dystrophic skeletal muscle. J. Clin. Pathol. 63, 805-813
  13. Mozzetta, C., Minetti, G., and Puri, P. L. (2009) Regenerative pharmacology in the treatment of genetic diseases: the paradigm of muscular dystrophy. Int. J. Biochem. Cell Biol. 41, 701-710
  14. Fyrst, H., and Saba, J. D. (2010) An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol 6, 489-497
  15. Xia, P., and Wadham, C. (2011) Sphingosine 1-phosphate, a key mediator of the cytokine network: juxtacrine signaling. Cytokine Growth Factor Rev. 22, 45-53
  16. Chi, H. (2011) Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol. Sci. 32, 16-24
  17. Nagata, Y., Partridge, T., Matsuda, R., and Zammit, P. (2006) Entry of muscle satellite cells into the cell cycle requires sphingolipid signaling. J. Cell Biol. 174, 245-253
  18. Lee, M. J., Thangada, S., Paik, J. H., Sapkota, G. P., Ancellin, N., Chae, S. S., Wu, M., Morales-Ruiz, M., Sessa, W. C., Alessi, D. R., and Hla, T. (2001) Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol. Cell 8, 693-704
  19. Van Brocklyn, J. R., Lee, M. J., Menzeleev, R., Olivera, A., Edsall, L., Cuvillier, O., Thomas, D. M., Coopman, P. J., Thangada, S., Liu, C. H., Hla, T., and Spiegel, S. (1998) Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. J. Cell Biol. 142, 229-240
  20. Matsushita, K., Morrell, C. N., and Lowenstein, C. J. (2003) Sphingosine 1-phosphate activates Weibel-Palade body exocytosis. Proc Natl Acad Sci USA 101, 11483–11487
  21. Kono, M., Mi, Y., Liu, Y., Sasaki, T., Allende, M. L., Wu, Y. P., Yamashita, T., and Proia, R. L. (2004) The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J. Biol. Chem. 279, 29367-29373
  22. Bencini, C., Squecco, R., Piperio, C., Formigli, L., Meacci, E., Nosi, D., Tiribilli, B., Vassalli, M., Quercioli, F., Bruni, P., Zecchi Orlandini, S., and Francini, F. (2003) Effects of sphingosine 1-phosphate on excitation-contraction coupling in mammalian skeletal muscle. J. Muscle Res. Cell Motil. 24, 539-554
  23. Birchwood, C. J., Saba, J. D., Dickson, R. C., and Cunningham, K. W. (2001) Calcium influx and signaling in yeast stimulated by intracellular sphingosine 1-phosphate accumulation. J. Biol. Chem. 276, 11712-11718
  24. Bruni, P., and Donati, C. (2008) Pleiotropic effects of sphingolipids in skeletal muscle. Cell. Mol. Life Sci. 65, 3725-3736
  25. Zanin, M., Germinario, E., Dalla Libera, L., Sandona, D., Sabbadini, R. A., Betto, R., and Danieli-Betto, D. (2008) Trophic action of sphingosine 1-phosphate in denervated rat soleus muscle. Am J Physiol Cell Physiol 294, C36-46
  26. Bolz, S. S., Vogel, L., Sollinger, D., Derwand, R., Boer, C., Pitson, S. M., Spiegel, S., and Pohl, U. (2003) Sphingosine kinase modulates microvascular tone and myogenic responses through activation of RhoA/Rho kinase. Circulation 108, 342-347
  27. Herr, D. R., Fyrst, H., Phan, V., Heinecke, K., Georges, R., Harris, G. L., and Saba, J. D. (2003) Sply regulation of sphingolipid signaling molecules is essential for Drosophila development. Development 130, 2443-2453
  28. Fyrst, H., Zhang, X., Herr, D. R., Byun, H. S., Bittman, R., Phan, V. H., Harris, G. L., and Saba, J. D. (2008) Identification and characterization by electrospray mass spectrometry of endogenous Drosophila sphingadienes. J. Lipid Res. 49, 597-606

Revised: December 1, 2016 3:25 PM

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