T.P.12 Dietary phosphate intake and exercise-induced stress induce severe muscle necrosis in adult mdx mice

Abstract

Progressive muscle degeneration, ectopic calcification in skeletal muscle, and high serum phosphate levels are characteristic features of muscular dystrophy especially in mdx mice. However, the effects of dietary phosphate intake on ectopic calcification and muscle pathology are not well studied. We previously reported that increased dietary phosphate intake caused elevated serum phosphate (Pi) levels, severe ectopic calcification and reduced muscle function in mdx mice. In contrast, lowering phosphate intake ameliorated the pathogenesis of the mice. In this study, we examined the effects of dietary phosphate intake and exercise-induced stress on muscle pathology of 90days old mdx mice (adult mdx mice). Voluntary running on activity wheel (VR) increases physical activity and negatively affects muscle pathology of the mice. We found that 10days of VR exacerbated muscle degeneration, increased macrophage infiltration and increased ectopic calcification in limb muscles of high-phosphate fed adult mdx mice. Tibialis anterior (TA) muscle, which consists mostly of muscle fibers with central nuclei and minimal necrotic areas when the mice were kept in a normal cage, was the most affected muscle by VR. Since numerous muscle fibers were embryonic heavy chain positive, high-phosphate intake did not interfere with muscle regeneration but dramatically progressed muscle degeneration. Interestingly, exercise and low-phosphate intake had relatively few areas of group degeneration and no ectopic calcification in TA muscle of mdx mice. The muscle pathologies of the exercised and non-exercised mdx mice fed low-Pi diet were similar. Therefore we conclude that high dietary phosphate intake progresses the pathogenesis of muscular dystrophy, and lowering phosphate intake could increase resistance to exercise-induced damage.