title: Whole body periodic acceleration is an effective therapy to ameliorate muscular dystrophy in mdx mice.
abstract: Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin in both skeletal and cardiac muscles. This leads to severe muscle degeneration, and dilated cardiomyopathy that produces patient death, which in most cases occurs before the end of the second decade. Several lines of evidence have shown that modulators of nitric oxide (NO) pathway can improve skeletal muscle and cardiac function in the mdx mouse, a mouse model for DMD. Whole body periodic acceleration (pGz) is produced by applying sinusoidal motion to supine humans and in standing conscious rodents in a headward-footward direction using a motion platform. It adds small pulses as a function of movement frequency to the circulation thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of NO. In this study, we examined the potential therapeutic properties of pGz for the treatment of skeletal muscle pathology observed in the mdx mouse. We found that pGz (480 cpm, 8 days, 1 hr per day) decreased intracellular Ca(2+) and Na(+) overload, diminished serum levels of creatine kinase (CK) and reduced intracellular accumulation of Evans Blue. Furthermore, pGz increased muscle force generation and expression of both utrophin and the carboxy-terminal PDZ ligand of nNOS (CAPON). Likewise, pGz (120 cpm, 12 h) applied in vitro to skeletal muscle myotubes reduced Ca(2+) and Na(+) overload, diminished abnormal sarcolemmal Ca(2+) entry and increased phosphorylation of endothelial NOS. Overall, this study provides new insights into the potential therapeutic efficacy of pGz as a non-invasive and non-pharmacological approach for the treatment of DMD patients through activation of the NO pathway.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Francisco
authors.initials: F
authors.lastname: Altamirano
authors.affiliation: Department of Anesthesiology Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Perez
authors.affiliation: Department of Physiology, Perleman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Genetics and Program in Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Widrick
authors.affiliation: Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Barton
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America; Department of Anesthesiology Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Allen
authors.affiliation: Division of Neonatology, Mount Sinai Medical Center, Miami, Florida, United States of America.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Adams
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America; Department of Anesthesiology Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Lopez
mesh_terms: D000054:Acceleration; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D006321:Heart / Q000503:physiopathology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009038:Motion; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000503:physiopathology / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne / Q000503:physiopathology / Q000628:therapy*; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D049411:Utrophin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C110667:Nos1ap protein, mouse; D049411:Utrophin; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D012964:Sodium; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse