title: Reduced resting potentials in dystrophic (mdx) muscle fibers are secondary to NF-κB-dependent negative modulation of ouabain sensitive Na+-K+ pump activity.
abstract: To examine potential mechanisms for the reduced resting membrane potentials (RPs) of mature dystrophic (mdx) muscle fibers, the Na(+)-K(+) pump inhibitor ouabain was added to freshly isolated nondystrophic and mdx fibers. Ouabain produced a 71% smaller depolarization in mdx fibers than in nondystrophic fibers, increased the [Na(+)](i) in nondystrophic fibers by 40%, but had no significant effect on the [Na(+)](i) of mdx fibers, which was approximately double that observed in untreated nondystrophic fibers. Western blots indicated no difference in total and phosphorylated Na(+)-K(+) ATPase catalytic α1 subunit between nondystrophic and mdx muscle. Examination of the effects of the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) indicated that direct application of the drug slowly hyperpolarized mdx fibers (7 mV in 90 min) but had no effect on nondystrophic fibers. Pretreatment with ouabain abolished this hyperpolarization, and pretreatment with PDTC restored ouabain-induced depolarization and reduced [Na(+)](i). Administration of an NF-κB inhibitor that utilizes a different mechanism for reducing nuclear NF-κB activation, ursodeoxycholic acid (UDCA), also hyperpolarized mdx fibers. These results suggest that in situ Na(+)-K(+) pump activity is depressed in mature dystrophic fibers by NF-κB dependent modulators, and that this reduced pump activity contributes to the weakness characteristic of dystrophic muscle.
authors.affiliation: Dept. of Physiology, Kirksville College of Osteopathic Medicine, A.T. Still University, Kirksville, MO 63501-1497, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Miles
authors.forename: E
authors.initials: E
authors.lastname: Cottey
authors.forename: A
authors.initials: A
authors.lastname: Cottey
authors.forename: C
authors.initials: C
authors.lastname: Stefanski
authors.forename: C G
authors.initials: CG
authors.lastname: Carlson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008839:Microelectrodes; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000502:physiology*; D010042:Ouabain / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D051996:Transcription Factor RelA; C020972:pyrrolidine dithiocarbamic acid; D010042:Ouabain; D014580:Ursodeoxycholic Acid; D004247:DNA; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase