Dietary Phosphorus Overload Aggravates the Phenotype of the Dystrophin-Deficient mdx Mouse

Abstract

Duchenne muscular dystrophy is a lethal X-linked disease with no effective treatment. Progressive muscle degeneration, increased macrophage infiltration, and ectopic calcification are characteristic features of the mdx mouse, a murine model of Duchenne muscular dystrophy. Because dietary phosphorus/phosphate consumption is increasing and adverse effects of phosphate overloading have been reported in several disease conditions, we examined the effects of dietary phosphorus intake in mdx mice phenotypes. On weaning, control and mdx mice were fed diets containing 0.7, 1.0, or 2.0 g phosphorus per 100 g until they were 90 days old. Dystrophic phenotypes were evaluated in cryosections of quadriceps and tibialis anterior muscles, and maximal forces and voluntary activity were measured. Ectopic calcification was analyzed by electron microscopy to determine the cells initially responsible for calcium deposition in skeletal muscle. Dietary phosphorus overload dramatically exacerbated the dystrophic phenotypes of mdx mice by increasing inflammation associated with infiltration of M1 macrophages. In contrast, minimal muscle necrosis and inflammation were observed in exercised mdx mice fed a low-phosphorus diet, suggesting potential beneficial therapeutic effects of lowering dietary phosphorus intake on disease progression. To our knowledge, this is the first report showing that dietary phosphorus intake directly affects muscle pathological characteristics of mdx mice. Dietary phosphorus overloading promoted dystrophic disease progression in mdx mice, whereas restricting dietary phosphorus intake improved muscle pathological characteristics and function.

Reduced mitochondrial respiration and increased calcium deposits in the EDL muscle, but not in soleus, from 12-week-old dystrophic mdx mice

“…1). Wada and colleagues (2014) described ~5% increase in calcium deposits in tibialis anterior muscle from mdx 20 . These results show that a high accumulation of calcium deposits may be specific to EDL from mdx at 12 wks.

Figure 1Calcium deposit quantification in soleus and EDL muscles from 4- and 12-wk-old control and mdx animals.

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Treatment with the anti-IL-6 receptor antibody attenuates muscular dystrophy via promoting skeletal muscle regeneration in dystrophin-/utrophin-deficient mice

“…Compared with mdx mice, there was a substantial amount of fibrotic tissue in the skeletal muscle of dKO mice. When compared, at the same age, the quadriceps muscle of mdx mice has a higher percentage of F4/80-positive inflammatory area than that of control dKO mice [ 40 ]. The action of pro- and anti-inflammatory cytokines in dystrophic muscle is distinguished in different ages and phases of the disease [ 41 , 42 ], so we analyzed the mRNA levels of inflammatory cytokines.…”

Whole-body clearing, staining and screening of calcium deposits in the mdx mouse model of Duchenne muscular dystrophy

“…Calcium deposits develop as this fatal disorder progresses, contributing to respiratory and/or cardiac muscle weakness and death. Therefore, many studies aimed at characterizing such deposits to improve our understanding of the molecular mechanisms of DMD development and find ways to stop its progression [ 13 – 16 ].…”