Abstract
A preclinical screening for prompt-to-use drugs that are safer than steroids and beneficial in Duchenne muscular dystrophy was performed. Compounds able to reduce calcium-induced degeneration (taurine or creatine 10% in chow) or to stimulate regeneration [insulin-like growth factor-1 (IGF-1); 50 or 500 μg/kg s.c.] were administered for 4 to 8 weeks to mdx mice undergoing chronic exercise on a treadmill, a protocol to worsen dystrophy progression. α-Methyl-prednisolone (PDN; 1 mg/kg) was used as positive control. The effects were evaluated in vivo on forelimb strength and in vitro electrophysiologically on the macroscopic chloride conductance (gCl), an index of degeneration-regeneration events in mdx muscles, and on the mechanical threshold, a calcium-sensitive index of excitation-contraction coupling. The exercise produced a significant weakness and an impairment of gCl, by further decreasing the already low value of degenerating diaphragm (DIA) and fully hampering the increase of gCl typical of regenerating extensor digitorum longus (EDL) mdx muscle. The already negative voltage threshold for contraction of mdx EDL was also slightly worsened. Taurine > creatine > IGF-1 counteracted the exercise-induced weakness. The amelioration of gCl was drug- and muscle-specific: taurine was effective in EDL, but not in DIA muscle; IGF-1 and PDN were fully restorative in both muscles, whereas creatine was ineffective. An acute effect of IGF-1 on gCl was observed in vitro in untreated, but not in IGF-1-treated exercised mdx muscles. Taurine > PDN > IGF-1, but not creatine, significantly ameliorated the negative threshold voltage values of the EDL fibers. The results predict a potential benefit of taurine and IGF-1 for treating human dystrophy.
Footnotes
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The financial support of Telethon-Italy to the project “Potential pharmacological approaches to muscular dystrophies: multifunctional evaluation of mechanism of action, efficacy and safety in animal models of the human diseases” (no. 1150) is gratefully acknowledged.
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DOI: 10.1124/jpet.102.041343
- Abbreviations:
- DMD
- Duchenne muscular dystrophy
- gCl
- resting chloride conductance
- DIA
- diaphragm
- EDL
- extensor digitorum longus muscle
- MT
- mechanical threshold
- e-c
- excitation-contraction
- IGF-1
- insulin-like growth factor-1
- PDN
- α-methylprednisolone
- Rm
- membrane resistance
- gK
- resting potassium conductance
- ANOVA
- analysis of variance
- TA
- tibialis anterior
- Received July 10, 2002.
- Accepted September 20, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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