Zoe White1, Chady H Hakim2, Marine Theret3, N Nora Yang4, Fabio Rossi3, Dan Cox5, Gordon A Francis6, Volker Straub5, Kathryn Selby7, Constadina Panagiotopoulos7, Dongsheng Duan8, Pascal Bernatchez9. 1. Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia (UBC), Vancouver, BC, Canada; Centre for Heart & Lung Innovation, St. Paul's Hospital, Vancouver, Canada. 2. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO; National Center for Advancing Translational Sciences, NIH, Rockville, MD. 3. Biomedical Research Centre, UBC, Vancouver, Canada. 4. National Center for Advancing Translational Sciences, NIH, Rockville, MD. 5. Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK. 6. Centre for Heart & Lung Innovation, St. Paul's Hospital, Vancouver, Canada; Department of Medicine, UBC, Vancouver, Canada. 7. Department of Pediatrics, University of British Columbia (UBC), BC Children's Hospital Research Institute, Vancouver, Canada. 8. Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO; Department of Pediatrics, University of British Columbia (UBC), BC Children's Hospital Research Institute, Vancouver, Canada; Department of Neurology, University of Missouri, Columbia, MO; Department of Bioengineering, Faculty of Medicine, University of Missouri, Columbia, MO; Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO. Electronic address: duand@missouri.edu. 9. Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia (UBC), Vancouver, BC, Canada; Centre for Heart & Lung Innovation, St. Paul's Hospital, Vancouver, Canada. Electronic address: pascal.bernatchez@ubc.ca.
Abstract
BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive muscle diseases caused by mutations in the DMD gene, with DMD being the more severe form. We have recently shown that increased plasma low-density lipoprotein-associated cholesterol causes severe muscle wasting in the mdx mouse, a mild DMD model, which suggested that plasma lipids may play a critical role in DMD. We have also observed that loss of dystrophin in mice causes unexpected elevations in plasma lipoprotein levels. OBJECTIVE: The objectives of the study were to determine whether patients with DMD and BMD also present with clinically relevant plasma lipoprotein abnormalities and to mitigate the presence of confounders (medications and lifestyle) by analyzing the plasma from patients with DMD/BMD and unmedicated dogs with DMD, the most relevant model of DMD. METHODS: Levels of low-density lipoprotein-associated cholesterol, high-density lipoprotein cholesterol, and triglycerides were analyzed in patients with DMD and BMD and female carriers. Samples from unmedicated, ambulatory dogs with DMD, unaffected carriers, and normal controls were also analyzed. RESULTS: We report that 97% and 64% of all pediatric patients with DMD (33 of 36) and BMD (6 of 11) are dyslipidemic, along with an unusually high incidence in adult patients with BMD. All dogs with DMD showed plasma lipid abnormalities that progressively worsened with age. Most strikingly, unaffected carrier dogs also showed plasma lipid abnormalities similar to affected dogs with DMD. Dyslipidemia is likely not secondary to liver damage as unaffected carriers showed no plasma aminotransferase elevation. CONCLUSIONS: The high incidence of plasma lipid abnormalities in dystrophin-deficient plasma may depict a new type of genetic dyslipidemia. Abnormal lipid levels in dystrophinopathic samples in the absence of muscle damage suggest a primary state of dyslipidemia. Whether dyslipidemia plays a causal role in patients with DMD warrants further investigation, which could lead to new diagnostic and therapeutic options.
BACKGROUND:Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive muscle diseases caused by mutations in the DMD gene, with DMD being the more severe form. We have recently shown that increased plasma low-density lipoprotein-associated cholesterol causes severe muscle wasting in the mdx mouse, a mild DMD model, which suggested that plasma lipids may play a critical role in DMD. We have also observed that loss of dystrophin in mice causes unexpected elevations in plasma lipoprotein levels. OBJECTIVE: The objectives of the study were to determine whether patients with DMD and BMD also present with clinically relevant plasma lipoprotein abnormalities and to mitigate the presence of confounders (medications and lifestyle) by analyzing the plasma from patients with DMD/BMD and unmedicated dogs with DMD, the most relevant model of DMD. METHODS: Levels of low-density lipoprotein-associated cholesterol, high-density lipoprotein cholesterol, and triglycerides were analyzed in patients with DMD and BMD and female carriers. Samples from unmedicated, ambulatory dogs with DMD, unaffected carriers, and normal controls were also analyzed. RESULTS: We report that 97% and 64% of all pediatric patients with DMD (33 of 36) and BMD (6 of 11) are dyslipidemic, along with an unusually high incidence in adult patients with BMD. All dogs with DMD showed plasma lipid abnormalities that progressively worsened with age. Most strikingly, unaffected carrier dogs also showed plasma lipid abnormalities similar to affected dogs with DMD. Dyslipidemia is likely not secondary to liver damage as unaffected carriers showed no plasma aminotransferase elevation. CONCLUSIONS: The high incidence of plasma lipid abnormalities in dystrophin-deficient plasma may depict a new type of genetic dyslipidemia. Abnormal lipid levels in dystrophinopathic samples in the absence of muscle damage suggest a primary state of dyslipidemia. Whether dyslipidemia plays a causal role in patients with DMD warrants further investigation, which could lead to new diagnostic and therapeutic options.
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