Effect of 2-Aminoethoxydiphenyl Borate on the State of Skeletal Muscles in Dystrophin-Deficient Mice.

OBJECTIVE

Ca overload of muscle fibers is one of the factors that secondarily aggravate the development of Duchenne muscular dystrophy (DMD). The purpose of this study is to evaluate the effects of the Ca channel modulator 2-aminoethoxydiphenyl borate (APB) on skeletal muscle pathology in dystrophin-deficient mice.

METHODS

Mice were randomly divided into six groups: wild type (WT), WT+3 mg/kg APB, WT+10 mg/kg APB, , +3 mg/kg APB, +10 mg/kg APB. APB was administered intraperitoneally daily for 28 days. Finally, we assessed the grip strength and hanging time of mice, the histology and ultrastructure of the quadriceps, as well as the parameters reflecting quadricep mitochondrial function.

RESULTS

3 mg/kg APB was shown to reduce creatine kinase activity in the serum, intensity of degeneration and the level of fibrosis in the quadriceps of mice, and improved tissue ultrastructure. However, this effect of APB was not sufficient to improve grip strength and hanging time of mice. The effect of 3 mg/kg APB may be due to improve Ca homeostasis in skeletal muscles, as evidenced by a trend toward decreased Ca overload of quadricep mitochondria. High dose of APB (10 mg/kg body weight) showed less pronounced effect on the pathological phenotype of mice. Moreover, 10 mg/kg APB disrupted the ultrastructure of the quadriceps and caused a decrease in grip strength in WT mice.

CONCLUSIONS

APB is able to improve the phenotype in mouse DMD model. However, the effect of APB is quite limited, which may be due to its multitargeting of Ca channels in the membranes of muscle fibers and intracellular organelles, differentially expressed in DMD.