title: Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function.
abstract: Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long-term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin-loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.
authors: 2Center for Translational Research in Advanced Imaging and Nanomedicine, Department of Medicine, Washington University School of Medicine, 660 South Euclid Ave., Saint Louis, MO 63110 USA. saw@wuphys.wustl.edu.
authors: Kristin P
authors: KP
authors: Bibee
authors: Ya-Jian
authors: YJ
authors: Cheng
authors: James K
authors: JK
authors: Ching
authors: Jon N
authors: JN
authors: Marsh
authors: Allison J
authors: AJ
authors: Li
authors: Richard M
authors: RM
authors: Keeling
authors: Anne M
authors: AM
authors: Connolly
authors: Paul T
authors: PT
authors: Golumbek
authors: Jacob W
authors: JW
authors: Myerson
authors: Grace
authors: G
authors: Hu
authors: Junjie
authors: J
authors: Chen
authors: William D
authors: WD
authors: Shannon
authors: Gregory M
authors: GM
authors: Lanza
authors: Conrad C
authors: CC
authors: Weihl
authors: Samuel A
authors: SA
authors: Wickline
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death; D003402:Creatine Kinase / Q000378:metabolism; D016503:Drug Delivery Systems; D005355:Fibrosis / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D053580:Muscle Strength; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000473:pathology; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D012038:Regeneration; D020123:Sirolimus / Q000008:administration & dosage*; D014018:Tissue Distribution
chemical_list: D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D003402:Creatine Kinase; D020123:Sirolimus
keywords: Duchenne; cardiomyopathy; drug delivery; nanomedicine; perfluorocarbon