Age‐dependent changes in metabolite profile and lipid saturation in dystrophic mice

Abstract

Duchenne Muscular Dystrophy (DMD) is a fatal X-linked genetic disorder. In DMD, the absence of the dystrophin protein causes decreased sarcolemmal integrity resulting in progressive replacement of muscle with fibrofatty tissue. The effects of lacking dystrophin on muscle and systemic metabolism are still unclear. Therefore, to determine the impact of the absence of dystrophin on metabolism, we investigated the metabolic and lipid profile at two different, well-defined stages of muscle damage and stabilization in mdx mice. We measured NMR-detectable metabolite and lipid profiles in the serum and muscles of mdx mice at 6 and 24 weeks of age. Metabolites were determined in muscle in vivo using 1 H MRI/MRS, in isolated muscles using 1 H-HR-MAS NMR, and in serum using high resolution 1 H/ 13 C NMR. Dystrophic mice were found to have a unique lipid saturation profile compared with control mice, revealing an age-related metabolic change. In the 6-week-old mdx mice, serum lipids were increased and the degree of lipid saturation changed between 6 and 24 weeks.The serum taurine-creatine ratio increased over the life span of mdx, but not in control mice. Furthermore, the saturation index of lipids increased in the serum but decreased in the tissue over time. Finally, we demonstrated associations between MRI-T 2 , a strong indicator of inflammation/edema, with tissue and serum lipid profiles. These results indicate the complex temporal changes of metabolites in the tissue and serum during repetitive bouts of muscle damage and regeneration that occur in dystrophic muscle.

Cholesterol metabolism is a potential therapeutic target in Duchenne Muscular Dystrophy

“…However, our investigation is in agreement with earlier reports in support of lipids and particularly of cholesterol metabolism abnormalities in DMD 13,14,[106][107][108][109][110][111][112]15,20,[100][101][102][103][104][105] . Of particular interest, Steen and colleagues reported the improved dystrophic parameters in an mdx mouse that overexpress the NPC1 gene, an accelerator of intracellular cholesterol trafficking 113 , while Milad and colleagues reported the correlation between increased plasma cholesterol and accentuated muscular dystrophy in the mdx mouse 112 , which together supporting that perturbation of cholesterol metabolism affects the DMD phenotype.…”

Single‐cell RNA sequencing and lipidomics reveal cell and lipid dynamics of fat infiltration in skeletal muscle

“…At the same time, we found that the content of C18:2 associated with TAGs was significantly increased. The unsaturation index in the lipids showed a decreased trend in gastrocnemius muscle from 6‐week‐old MDX mice but increases more quickly in 24‐week‐old MDX mice vs. controls 58 . We found that ectopic adipose tissue induced by GLY injection significantly decreased the percentages of SFAs and MUFAs, while it significantly increased PUFAs in muscle.…”

Integrated Metabolomics and Transcriptomics Suggest the Global Metabolic Response to 2-Aminoacrylate Stress in Salmonella enterica

“…To that end, untargeted metabolomics and comparative transcriptomics data are increasingly being used as the basis for building metabolic models that describe the physiological state of a cell [4][5][6]. Examples of this approach can be found in disciplines ranging from mammalian genetic disorders and cancer biology, to antibiotic modes of action and pathogen-host interaction [7][8][9][10]. While these analyses can contribute to defining the response to various cellular perturbations [11,12], they are most significant when confirmed by rigorous genetic, biochemical, and molecular biological experimentation.…”