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Research Article

A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

Nicholas P. Whitehead, Min Jeong Kim, Kenneth L. Bible, Marvin E. Adams, and Stanley C. Froehner
PNAS first published September 28, 2015; https://doi.org/10.1073/pnas.1509536112
Nicholas P. Whitehead
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195
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  • For correspondence: npwhite@uw.edu
Min Jeong Kim
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195
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Kenneth L. Bible
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195
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Marvin E. Adams
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195
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Stanley C. Froehner
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195
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  1. Edited by Gerald D. Fischbach, The Simons Foundation, New York, NY, and approved August 24, 2015 (received for review May 15, 2015)

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Significance

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease for which there is no effective treatment. Statins have been used for decades to improve cardiovascular health. In addition to lowering blood cholesterol levels, statins also reduce inflammation, oxidative stress, and fibrosis. These pathogenic processes all contribute to functional decline in DMD muscles. Therefore, we reasoned that statins could be a beneficial treatment for dystrophic muscles. In this study, we show that simvastatin dramatically improves muscle strength and fatigue resistance in DMD (mdx) mice. This result was accompanied by significantly reduced inflammation, oxidative stress, and fibrotic deposition in old, degenerated mdx muscle. These findings indicate that simvastatin is a promising, novel therapeutic approach for DMD and related muscle disorders.

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.

  • statin
  • muscular dystrophy
  • fibrosis
  • inflammation
  • muscle force

Footnotes

  • ↵1To whom correspondence should be addressed. Email: npwhite{at}uw.edu.
  • Author contributions: N.P.W. and S.C.F. designed research; N.P.W., M.J.K., K.L.B., and M.E.A. performed research; N.P.W., M.J.K., and M.E.A. analyzed data; and N.P.W. and S.C.F. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1509536112/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Simvastatin improves muscular dystrophy
Nicholas P. Whitehead, Min Jeong Kim, Kenneth L. Bible, Marvin E. Adams, Stanley C. Froehner
Proceedings of the National Academy of Sciences Sep 2015, 201509536; DOI: 10.1073/pnas.1509536112

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Simvastatin improves muscular dystrophy
Nicholas P. Whitehead, Min Jeong Kim, Kenneth L. Bible, Marvin E. Adams, Stanley C. Froehner
Proceedings of the National Academy of Sciences Sep 2015, 201509536; DOI: 10.1073/pnas.1509536112
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