Imatinib attenuates skeletal muscle dystrophy in mdx mice.
Duchenne-Meryon muscular dystrophy (DMD) is the most common and lethal genetic muscle disease. Ameliorating muscle necrosis, inflammation, and fibrosis represents an important therapeutic approach for DMD. Imatinib, an antineoplastic agent, demonstrated antiinflammatory and antifibrotic effects in liver, kidney, lung, and skin of various animal models. This study tested antiinflammatory and antifibrotic effects of imatinib in mdx mice, a DMD mouse model. We treated mdx mice with intraperitoneal injections of imatinib at the peak of limb muscle inflammation and the onset of diaphragm fibrosis. Controls received PBS vehicle or were left untreated. Muscle necrosis, inflammation, fibrosis, and function were evaluated by measuring serum CK activity, endomysial CD45 immunoreactive inflammation area, endomysial collagen III deposition, and hind limb grip strength. Phosphorylation of the tyrosine kinase targets of imatinib was assessed by Western blot in diaphragm tissue and in primary cultures of peritoneal macrophages and skeletal muscle fibroblasts. Imatinib markedly reduced muscle necrosis, inflammation, and fibrosis, and significantly improved hind limb grip strength in mdx mice. Reduced clinical disease was accompanied by inhibition of c-abl and PDGFR phosphorylation and suppression of TNF-alpha and IL-1beta expression. Imatinib therapy for DMD may hold promise for ameliorating muscle necrosis, inflammation, and fibrosis by inhibiting c-abl and PDGFR signaling pathways and downstream inflammatory cytokine and fibrotic gene expression.
Huang
Ping
P
Department of Neurology/Neurological Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195 USA.
Zhao
Xinyu S
XS
Fields
Matthew
M
Ransohoff
Richard M
RM
Zhou
Lan
L
D000818:Animals; D001483:Base Sequence; D001549:Benzamides; D003402:Creatine Kinase / Q000097:blood; D003964:Diaphragm / Q000187:drug effects / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D001549:Benzamides; D053583:Interleukin-1beta; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl; D003402:Creatine Kinase