title: A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy.
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.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195 npwhite@uw.edu.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Whitehead
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Bible
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195.
authors.forename: Marvin E
authors.initials: ME
authors.lastname: Adams
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195.
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Froehner
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D009097:Multienzyme Complexes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D053580:Muscle Strength / Q000187:drug effects*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009097:Multienzyme Complexes; D019821:Simvastatin; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D003402:Creatine Kinase
keywords: fibrosis; inflammation; muscle force; muscular dystrophy; statin