Muscle regeneration in dystrophic mdx mice is enhanced by isosorbide dinitrate.
Activation of muscle satellite cells, a fundamental step in the success of muscle regeneration is mediated by nitric oxide (NO). In this study, we investigated whether isosorbide dinitrate (ISD), an NO donor, could improve muscle regeneration in dystrophic mdx mice. The right tibialis anterior muscle of mdx and C57Bl/10 mice was injected with bupivacaine (0.3 ml, 33 mg/kg), a myotoxic agent, to induce muscle fiber regeneration. After bupivacaine injection, mice were treated with ISD (30 mg/kg; i.p.), verapamil (a non-NO donor vasodilator, 15 mg/kg, i.p.) or saline solution (vehicle, 0.3 ml, i.p.) for 20 days. Some bupivacaine-injected mice received no pharmacological treatment (control group). Muscle regeneration was evaluated by counting the total number of muscle fibers and measuring myofiber cross-sectional area. ISD significantly improved bupivacaine-induced muscle regeneration in mdx by increasing by 20% the total number of muscle fibers compared to the other groups. Spontaneous muscle regeneration, evaluated in the contralateral non-injected muscle, was not affected. ISD treatment did not affect myofiber cross-sectional area. Verapamil and saline had no effect on muscle regeneration. These results suggested that NO derived from ISD stimulated and/or recruited satellite cells. Pharmacological treatment with ISD could be clinically useful for improving muscle regeneration in Duchenne muscular dystrophy.
Marques
Maria Julia
MJ
Departamento de Anatomia, Instituto de Biologia, Universidade Estadual de Campinas, CP 6109, Campinas 13084-971, São Paulo, Brazil. marques@unicamp.br
Luz
Marcus Alexandre Mendes
MA
Minatel
Elaine
E
Neto
Humberto Santo
HS
D000779:Anesthetics, Local / Q000633:toxicity; D000818:Animals; D002045:Bupivacaine / Q000633:toxicity; D007548:Isosorbide Dinitrate / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy*; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D012038:Regeneration / Q000187:drug effects*
D000779:Anesthetics, Local; D020030:Nitric Oxide Donors; D007548:Isosorbide Dinitrate; D002045:Bupivacaine