Diltiazem and verapamil protect dystrophin-deficient muscle fibers of MDX mice from degeneration: a potential role in calcium buffering and sarcolemmal stability.
The lack of dystrophin in mdx mice and in Duchenne muscular dystrophy causes sarcolemmal breakdown and increased calcium influx followed by myonecrosis. We examined whether the calcium channel blockers diltiazem and verapamil protect dystrophic muscles from degeneration. Mdx mice received daily intraperitoneal injections of diltiazem or verapamil for 18 days, followed by removal of the sternomastoid, diaphragm, tibialis anterior, and cardiac muscles. Control mdx mice were injected with saline. Both drugs significantly decreased blood creatine kinase levels. Total calcium content was significantly higher in mdx muscles than in control C57Bl/10. Verapamil and diltiazem reduced total calcium content only in diaphragm and cardiac muscle. Histological analysis showed that diltiazem significantly attenuated myonecrosis in diaphragm. Immunoblots showed a significant increase of calsequestrin and beta-dystroglycan levels in some diltiazem- and verapamil-treated muscles. Possible interactions of these drugs with the sarcoplasmic reticulum and sarcolemma may also contribute to the improvement of the dystrophic phenotype.
Matsumura
Cintia Yuri
CY
Departamento de Anatomia, Instituto de Biologia, Universidade Estadual de Campinas (UNICAMP), Campinas, São Paulo, 13083-970, Brazil.
Pertille
Adriana
A
Albuquerque
Tereza C P
TC
Santo Neto
Humberto
H
Marques
Maria Julia
MJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002155:Calsequestrin / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D004110:Diltiazem / Q000627:therapeutic use*; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009137:Muscular Dystrophy, Animal / Q000473:pathology* / Q000517:prevention & control*; D012508:Sarcolemma / Q000187:drug effects* / Q000378:metabolism; D014700:Verapamil / Q000627:therapeutic use*
D002121:Calcium Channel Blockers; D002155:Calsequestrin; D049030:Dystroglycans; D014700:Verapamil; D003402:Creatine Kinase; D004110:Diltiazem; D002118:Calcium