Strength and corticosteroid responsiveness of mdx mice is unchanged by RAG2 gene knockout.
Corticosteroids improve muscle function in boys with Duchenne muscular dystrophy and mdx mice possibly via effects on T-cell and B-cells. We quantified T-cell/B-cell functional effects and refined prednisolone's therapeutic mechanism in mdx mice. RAG2(-/-) mice, which produce no T-cells or B-cells, were crossed with mdx mice, which lack dystrophin protein. Strength testing (3-36 weeks) was performed on treated and control groups of male mdx RAG2(-/-)and mdx RAG2(+/-) mice. Longitudinal grip strength testing and hanging wire testing were assessed. Voluntary wheel running and creatine kinase level were measured. The absence of T-cells/B-cells (RAG2(-/-) mutation) caused no physiologic improvement. Prednisolone improved performance in mdx mice, independent of RAG2 gene expression (+ or -/-). Prednisolone treatment increased the frequency of muscle calcification, while RAG2 genotype had no effect. There was no change in fiber type proportions due to RAG2 genotype or prednisolone treatment. Thus, T-cells and/or B-cells (and immunoglobulins), while demonstrable in mdx mouse muscle, are playing a negligible role in their mdx-related functional outcome. Prednisolone's therapeutic effect is through T-cell/B-cell independent mechanisms in mdx mice.
Golumbek
Paul T
PT
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. golumbekp@neuro.wustl.edu
Keeling
Richard M
RM
Connolly
Anne M
AM
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005260:Female; D005552:Forelimb / Q000187:drug effects* / Q000503:physiopathology; D005938:Glucocorticoids / Q000494:pharmacology*; D007136:Immunoglobulins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy*; D011239:Prednisolone / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects
D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D007136:Immunoglobulins; C499308:Rag2 protein, mouse; D011239:Prednisolone; D003402:Creatine Kinase