title: Na+ dysregulation coupled with Ca2+ entry through NCX1 promotes muscular dystrophy in mice.
abstract: Unregulated Ca(2+) entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na(+)-Ca(2+) exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd(-/-)), Dysf(-/-), and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd(-/-) mice. Measured increases in baseline Na(+) and Ca(2+) in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca(2+) influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca(2+) levels. Indeed, Atp1a2(+/-) (encoding Na(+)-K(+) ATPase α2) mice, which have reduced Na(+) clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na(+)-K(+) ATPase inhibitor digoxin. Treatment of Sgcd(-/-) mice with ranolazine, a broadly acting Na(+) channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital, and Howard Hughes Medical Institute, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Burr
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Millay
authors.forename: Sanjeewa A
authors.initials: SA
authors.lastname: Goonasekera
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sargent
authors.forename: James
authors.initials: J
authors.lastname: Collins
authors.forename: Francisco
authors.initials: F
authors.lastname: Altamirano
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
authors.forename: Paul D
authors.initials: PD
authors.lastname: Allen
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
authors.forename: José Rafael
authors.initials: JR
authors.lastname: López
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004077:Digoxin / Q000494:pharmacology; D000073939:Dysferlin; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006614:Hindlimb / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D000069458:Ranolazine; D049031:Sarcoglycans / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000083:Acetanilides; C497505:Dysf protein, mouse; D000073939:Dysferlin; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C499849:NCX1 protein, mouse; D010879:Piperazines; D049031:Sarcoglycans; D026941:Sodium Channel Blockers; D019831:Sodium-Calcium Exchanger; D004077:Digoxin; D012964:Sodium; D000069458:Ranolazine; C401838:Atp1a2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium