Abstract
Duchenne muscular dystrophy (DMD) is a rare genetic disorder affecting paediatric patients. The disease course is characterized by loss of muscle mass, which is rapidly substituted by fibrotic and adipose tissue. Clinical and preclinical models have clarified the processes leading to muscle damage and myofiber degeneration. Analysis of the fat component is however emerging as more evidence shows how muscle fat fraction is associated with patient performance and prognosis. In this article we aimed to study whether alterations exist in the composition of lipids in plasma samples obtained from mouse models. Analysis of plasma samples was performed in 4 mouse models of DMD and wild-type mice by LC–MS. Longitudinal samplings of individual mice covering an observational period of 7 months were obtained to cover the different phases of the disease. We report clear elevation of glycerolipids and glycerophospholipids families in dystrophic mice compared to healthy mice. Triacylglycerols were the strongest contributors to the signatures in mice. Annotation of individual lipids confirmed the elevation of lipids belonging to these families as strongest discriminants between healthy and dystrophic mice. A few sphingolipids (such as ganglioside GM2, sphingomyelin and ceramide), sterol lipids (such as cholesteryl oleate and cholesteryl arachidonate) and a fatty acyl (stearic acid) were also found to be affected in dystrophic mice. Analysis of serum and plasma samples show how several lipids are affected in dystrophic mice affected by muscular dystrophy. This study sets the basis to further investigations to understand how the lipid signature relates to the disease biology and muscle performance.
Highlights
A few reports investigated the lipid content in Duchenne muscular dystrophy (DMD) skeletal muscle
The obtained data support the investigation of circulating lipids in larger animal models as well as in patients affected by Duchenne muscular dystrophy
Sample volumes did not allow analysis of mdx samples at 18 weeks of age, only 4 time points were available for mdx mice. Another 3 mdx mouse models carrying 2, 1 or no functional alleles coding for the dystrophin paralog utrophin were included, as these mice show somewhat different progression due to dose dependent compensation by functional utrophin alleles
Summary
A few reports investigated the lipid content in DMD skeletal muscle. An increase in sphingomyelin, cholesterol, triglycerides and reduced acylation of phosphatidylcholine with linoleic acid was consistently reported in previous studies in muscle biopsies[19,20,21,22]. Given that associations in the composition of lipids between serum and muscle have been described[24], we focused our investigation on blood samples, which offer the possibility to obtain repeated samplings and observe changes during follow-up visits. The signature was further investigated in additional mouse models with a different genetic background carrying 2, 1 or no functional copies of the Utrn gene, encoding the dystrophin paralog utrophin. As utrophin can partly compensate for lack of dystrophin in mice, Utrn up-regulation has been proposed as therapeutic strategy for DMD; the mice included in this study have been previously shown to have subtle phenotypic differences related to the copy number of functional Utrn[25, 26]. The obtained data support the investigation of circulating lipids in larger animal models as well as in patients affected by Duchenne muscular dystrophy
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