Chronic treatment with agents that stabilize cytosolic IκB-α enhances survival and improves resting membrane potential in MDX muscle fibers subjected to chronic passive stretch

Abstract

The potential pathogenic role of increased NFκB signaling in passively stretched dystrophic skeletal muscle was examined by treating adult mdx mice with an agent that stabilized cytosolic IκB-α (pyrollidine dithiocarbamate, PDTC)and examining the effects of this treatment on the chronically stretched mdx triangularis sterni (TS) muscle. Daily PDTC treatment significantly increased the number of surviving striated TS fibers regardless of age. TS fibers from untreated mdx mice had significantly lower resting potentials (RPs) than nondystrophic mice. Treatment with GdCl3 to block resting Ca2+ influx had no effect on RP in either nondystrophic or mdx preparations. Daily treatment with PDTC significantly improved the RP regardless of age. These results are consistent with the hypothesis that passive stretch activates an NFκB-mediated pathogenic mechanism in dystrophic muscle and suggest that agents which stabilize cytosolic IκB-α levels may be useful for treating Duchenne and related muscular dystrophies.

Keywords

• Duchenne muscular dystrophy
• mdx Mouse
• Dystrophinopathies
• NFκB
• IκB-α
• Pyrollidine dithiocarbamate