Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors

Abstract

Pharmacological interventions that increase myofiber size counter the functional decline of dystrophic muscles1,2. We show that deacetylase inhibitors increase the size of myofibers in dystrophin-deficient (MDX) and α-sarcoglycan (α-SG)–deficient mice by inducing the expression of the myostatin antagonist follistatin3 in satellite cells. Deacetylase inhibitor treatment conferred on dystrophic muscles resistance to contraction-coupled degeneration and alleviated both morphological and functional consequences of the primary genetic defect. These results provide a rationale for using deacetylase inhibitors in the pharmacological therapy of muscular dystrophies.

Figure 1: TSA treatment restores muscle function and morphology in MDX mice.
Figure 2: Induction of follistatin mediates the increased efficiency of myotube formation from satellite cells derived by myofibers of dystrophic muscles.

References

  1. 1

    Engvall, E. & Wewer, U.M. FASEB J. 17, 1579–1584 (2003).

    CAS  Article  Google Scholar 

  2. 2

    Zammit, P.S. & Partridge, T.A. Nat. Med. 8, 1355–1356 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Lee, S.J. Annu. Rev. Cell Dev. Biol. 20, 61–86 (2004).

    CAS  Article  Google Scholar 

  4. 4

    Bogdanovich, S. et al. Nature 420, 418–421 (2002).

    CAS  Article  Google Scholar 

  5. 5

    Wagner, K.R., McPherron, A.C., Winik, N. & Lee, S.J. Ann. Neurol. 52, 832–836 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Barton, E.R., Morris, L., Musaro, A., Rosenthal, N. & Sweeney, H.L. J. Cell Biol. 157, 137–148 (2002).

    CAS  Article  Google Scholar 

  7. 7

    Iezzi, S., Cossu, G., Nervi, C., Sartorelli, V. & Puri, P.L. Proc. Natl. Acad. Sci. USA 99, 7757–7762 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Iezzi, S. et al. Dev. Cell 6, 673–684 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Emery, A.E. Lancet 359, 687–695 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Rafael, J.A., Tinsley, J.M., Potter, A.C., Deconinck, A.E. & Davies, K.E. Nat. Genet. 19, 79–82 (1998).

    CAS  Article  Google Scholar 

  11. 11

    Duclos, F. et al. J. Cell Biol. 142, 1461–1471 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Parsons, S.A., Millay, D.P., Sargent, M.A., McNally, E.M. & Molkentin, J.D. Am. J. Pathol. 168, 1975–1985 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Puri, P.L. et al. Mol. Cell 8, 885–897 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Canettieri, G. et al. Nat. Struct. Biol. 10, 175–181 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Saito, A. et al. Proc. Natl. Acad. Sci. USA 96, 4592–4597 (1999).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank K.P. Campbell (Howard Hughes Medical Institute, University of Iowa) for providing α-SG–deficient mice, G. Cossu. and E. Engvall for critically reading the manuscript, and Alberto Bordonaro for the art work on figures. P.L.P is an assistant Telethon scientist at the Dulbecco Telethon Institute. This work was supported by a Telethon Special Grant to P.L.P. and R.B.; Muscular Dystrophy Association, Parent Project Organization and Compagnia San Paolo di Torino grants to P.L.P.; a European Union Grant and a Telethon Grant to M.C.C.; an Associazione Italiana Ricerca sul Cancro Regional Grant to C.G.; Cariplo Foundation and Italian Space Agency grants to R.B.; and grants from the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the US National Institutes of Health to M.D.P and V.S.

Author information

Affiliations

Authors

Corresponding author

Correspondence to P L Puri.

Ethics declarations

Competing interests

P.G. and C.S. are employees of the Istituto di Ricerca di Biologia Molecolare—Merck Research Laboratories.

Supplementary information

Supplementary Fig. 1

Levels of histone acetylation in peripheral tissues of untreated and TSA, VPA or PHB-treated MDX mice. (PDF 199 kb)

Supplementary Fig. 2

Myogenic potential of satellite cells isolated from muscles of untreated and TSA, VPA or PHB-treated MDX mice. (PDF 1819 kb)

Supplementary Fig. 3

Improvement in muscle strength and function and levels of utrophin and dystrophin in untreated and TSA-treated MDX mice. (PDF 75 kb)

Supplementary Fig. 4

Distribution of fiber CSA and frequency histograms of single-fiber CSA in muscles from untreated and TSA-treated MDX mice. (PDF 78 kb)

Supplementary Fig. 5

Desmin-positive cells in muscle from untreated versus TSA-treated MDX mice. (PDF 55 kb)

Supplementary Fig. 6

Morphological and histological changes in muscles from untreated and TSA-treated MDX mice. (PDF 195 kb)

Supplementary Fig. 7

Myogenic potential of satellite cells isolated from muscles of α-SG–deficient mice untreated or TSA-treated; distribution of CSA and Azan Mallory staining of muscles from untreated and TSA-treated α-SG–deficient mice. (PDF 2836 kb)

Supplementary Fig. 8

Morphological and functional effects of MS 27-275 on MDX mice. (PDF 1144 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Minetti, G., Colussi, C., Adami, R. et al. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med 12, 1147–1150 (2006). https://doi.org/10.1038/nm1479

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing