Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1.
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 microg/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. alpha-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.
De Luca
Annamaria
A
Department of Pharmacobiology, Unit of Pharmacology, University of Bari, Bari, Italy. adeluca@farmbiol.uniba.it
Pierno
Sabata
S
Liantonio
Antonella
A
Cetrone
Michela
M
Camerino
Claudia
C
Fraysse
Bodvael
B
Mirabella
Massimo
M
Servidei
Serenella
S
Rüegg
Urs T
UT
Conte Camerino
Diana
D
D000818:Animals; D003401:Creatine / Q000627:therapeutic use; D018450:Disease Progression; D004594:Electrophysiology; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D018408:Patch-Clamp Techniques; D010805:Physical Conditioning, Animal / Q000502:physiology*; D013654:Taurine / Q000627:therapeutic use*
D007473:Ion Channels; D013654:Taurine; D007334:Insulin-Like Growth Factor I; D003401:Creatine