title: Long-term blocking of calcium channels in mdx mice results in differential effects on heart and skeletal muscle.
abstract: The disease mechanisms underlying dystrophin-deficient muscular dystrophy are complex, involving not only muscle membrane fragility, but also dysregulated calcium homeostasis. Specifically, it has been proposed that calcium channels directly initiate a cascade of pathological events by allowing calcium ions to enter the cell. The objective of this study was to investigate the effect of chronically blocking calcium channels with the aminoglycoside antibiotic streptomycin from onset of disease in the mdx mouse model of Duchenne muscular dystrophy (DMD). Treatment in utero onwards delayed onset of dystrophic symptoms in the limb muscle of young mdx mice, but did not prevent degeneration and regeneration events occurring later in the disease course. Long-term treatment had a positive effect on limb muscle pathology, reduced fibrosis, increased sarcolemmal stability, and promoted muscle regeneration in older mice. However, streptomycin treatment did not show positive effects in diaphragm or heart muscle, and heart pathology was worsened. Thus, blocking calcium channels even before disease onset does not prevent dystrophy, making this an unlikely treatment for DMD. These findings highlight the importance of analyzing several time points throughout the life of the treated mice, as well as analyzing many tissues, to get a complete picture of treatment efficacy.
authors.affiliation: Institute of Human Genetics, International Centre of Life, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Louise H
authors.initials: LH
authors.lastname: Jørgensen
authors.forename: Alison
authors.initials: A
authors.lastname: Blain
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Greally
authors.forename: Steve H
authors.initials: SH
authors.lastname: Laval
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blamire
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Davison
authors.forename: Heinrich
authors.initials: H
authors.lastname: Brinkmeier
authors.forename: Guy A
authors.initials: GA
authors.lastname: MacGowan
authors.forename: Henrik D
authors.initials: HD
authors.lastname: Schrøder
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D015220:Calcium Channels / Q000378:metabolism*; D003964:Diaphragm / Q000187:drug effects / Q000473:pathology; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D013307:Streptomycin / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002118:Calcium; D013307:Streptomycin