A long-term treatment with taurine prevents cardiac dysfunction in mdx mice

Abstract

Taurine is an amino acid abundantly present in heart and skeletal muscle. Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to skeletal muscle wasting and heart failure. An altered taurine metabolism has been described in dystrophic animals and short-term taurine administration exerts promising amelioration of early muscular alterations in the mdx mouse model of DMD. To reinforce the therapeutic and nutraceutical taurine potential in DMD, we evaluated the effects of a long-term treatment on cardiac and skeletal muscle function of mdx mice in a later disease stage. Taurine was administered in drinking water (1 g/kg/day) to wt and mdx mice for 6 months, starting at 6 months of age. Ultrasonography evaluation of heart and hind limb was performed, in parallel with in vivo and ex vivo functional tests and biochemical, histological and gene expression analyses. 12-month-old mdx mice showed a significant worsening of left ventricular function parameters (shortening fraction, ejection fraction, stroke volume), which were significantly counteracted by the taurine treatment. In parallel, histologic signs of damage were reduced by taurine along with the expression of proinflammatory myocardial IL-6. Interestingly, no effects were observed on hind limb volume and percentage of vascularization or on in vivo and ex vivo muscle functional parameters, suggesting a tissue-specific action of taurine in relation to the disease phase. A trend toward increase in taurine was found in heart and quadriceps from treated animals, paralleled by a slight decrease in mdx mice plasma. Our study provides evidences that taurine can prevent late heart dysfunction in mdx mice, further corroborating the interest on this amino acid toward clinical trials.

Keywords: CK = creatine kinase; CO, cardiac output; Cox4i1 = cytochrome c oxidase subunit IV isoform 1; Cs = citrate synthase; DGC = dystrophin-glycoprotein complex; DIA = diaphragm; DMD = Duchenne muscular dystrophy; EDL = extensor digitorum longus; EF = ejection fraction; Eef2 = eukaryotic translation elongation factor 2; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; GC = gastrocnemius muscle; IL-6 = interleukin 6; LDH = lactate dehydrogenase; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; PV = percentage of vascularization; ROS = reactive oxygen species; Rplp0 = ribosomal protein, large, P0; SF = shortening fraction; SV = stroke volume; Slc6a6 = solute carrier family 6 (neurotransmitter transporter; TauT = taurine transporter; cardiac output; taurine) member 6.