Leukemia inhibitory factor ameliorates muscle fiber degeneration in the mdx mouse

Abstract

Although the muscles of the mdx mouse lack dystrophin, the protein absent in muscles of humans affected with Duchenne muscular dystrophy (DMD), the only mdx muscle to degenerate in a manner similar to those of DMD boys is the diaphragm. We have previously shown that leukemia inhibitory factor (LIF) is a trauma factor that enhances muscle repair in vivo and, when applied exogenously, increases the fiber size of mdx skeletal muscle. Furthermore, we developed a controlled release device for LIF based on a calcium alginate rod (release rate about 0.5% per day). These rods were sutured to the abdominal surface of the hemidiaphragm of mdx mice 3 months old. At age 6 months the mice were killed and the diaphragm muscles fixed and sectioned. The sections showed obvious muscle degeneration at 3 months of age in mdx mouse diaphragms and further degeneration at 6 months in saline-perfused muscle. Hemidiaphragm muscles continuously exposed to LIF over the same period contained more normal myofibers, larger regenerated fibers, and less adipose tissue and other non-contractile tissue. Morphometric analysis of the diaphragm sections was carried out. The LIF-treated animals showed a significant increase in fiber number and size compared to saline rod controls. The amount of nonmuscle (connective tissue and adipose tissue) was significantly reduced and the maximum force-producing capacity of isolated diaphragm muscle strips was higher in LIF-treated mice. The results demonstrate that LIF treatment ameliorates the dystrophic abnormalities in mdx mouse diaphragm.