digoxin and Muscular-Dystrophy--Animal

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.

Topics: Acetanilides; Animals; Calcium; Digoxin; Dysferlin; Enzyme Inhibitors; Hindlimb; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Mice, Knockout; Muscle, Skeletal; Muscular Dystrophy, Animal; Piperazines; Ranolazine; Sarcoglycans; Sodium; Sodium Channel Blockers; Sodium-Calcium Exchanger; Sodium-Potassium-Exchanging ATPase

We estimated the effect of digoxin on the myocardial potassium content and the action potentials of the left ventricular papillary muscles in dystrophic mice (C57BL/6JCL dy X dy). All of 10 dystrophic mice died following ip injection of digoxin at a dose of one quarter of the iv LD50 for normal mice. The myocardial digoxin concentration and the myocardial potassium content in dystrophic mice were similar to those in normal mice before and 60 min after the ip injection of digoxin. The action potential durations (APD) in dystrophic mice were significantly longer than those in normal mice. Perfusion of digoxin (2 micrograms/ml) for 30 min reduced the APD significantly and induced arrhythmias in dystrophic mice, but it did not bring about any significant change in normal mice. These data suggest that dystrophic mice have increased sensitivity to digitalis. This hypersensitivity to digitalis is not due to increased myocardial digoxin uptake or decreased myocardial potassium content.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Digoxin; Female; Male; Mice; Mice, Inbred C57BL; Muscular Dystrophy, Animal; Myocardium; Papillary Muscles; Potassium; Sodium-Potassium-Exchanging ATPase

To clarify the abnormality of skeletal muscles in dystrophic mice, we studied the potassium content, resting membrane potential and especially the effects of digoxin on the membrane potential. Both the potassium content and the resting membrane potential of dystrophic muscles were significantly lower than those of normal mice. The resting membrane potential of dystrophic muscles was less reduced by digoxin than that of normal mice. It was suggested that there was a change in membrane permeability of skeletal muscles in dystrophic mice and that membrane permeability was less sensitive to digoxin than normal mice.

Topics: Animals; Cell Membrane Permeability; Digoxin; Female; Male; Membrane Potentials; Mice; Muscles; Muscular Dystrophy, Animal; Potassium