Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease
| Autor: | Angèle Nalbandian, Agnesa Avanesian, Tahseen Mozaffar, Kwang-Mook Jung, Christopher Nguyen, Virginia Kimonis, Daniele Piomelli, Katrina J. Llewellyn |
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| Rok vydání: | 2013 |
| Předmět: |
Heterozygote
medicine.medical_specialty Ceramide Offspring Valosin-containing protein Cell Cycle Proteins Biology Mice chemistry.chemical_compound Valosin Containing Protein Internal medicine Medicine and Health Sciences Autophagy Genetics medicine Animals Kyphosis Muscle Skeletal Myopathy Molecular Biology Genetic Association Studies Genetics (clinical) Adenosine Triphosphatases Mice Knockout Electromyography Homozygote Skeletal muscle Lipid metabolism Heterozygote advantage Articles General Medicine Lipid Metabolism Osteitis Deformans Diet Mitochondria Disease Models Animal medicine.anatomical_structure Endocrinology chemistry Immunology Disease Progression biology.protein medicine.symptom |
| Zdroj: | Llewellyn, Katrina J; Nalbandian, Angèle; Jung, Kwang-Mook; Nguyen, Christopher; Avanesian, Agnesa; Mozaffar, Tahseen; et al.(2014). Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. Human Molecular Genetics, 23(5), 1333-1344. doi: 10.1093/hmg/ddt523. UC Irvine: Institute for Clinical and Translational Science. Retrieved from: http://www.escholarship.org/uc/item/0cv5910p |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddt523 |
| Popis: | Valosin-containing protein (VCP)-associated disease caused by mutations in the VCP gene includes combinations of a phenotypically heterogeneous group of disorders such as hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP myopathy or dementia. VCP mouse models carrying the common R155H mutation include several of the features typical of the human disease. In our previous investigation, VCP(R155H/R155H) homozygous mice exhibited progressive weakness and accelerated pathology prior to their early demise. Herein, we report that feeding pregnant VCP(R155H/+) heterozygous dams with a lipid-enriched diet (LED) results in the reversal of the lethal phenotype in VCP(R155H/R155H) homozygous offspring. We examined the effects of this diet on homozygous and wild-type mice from birth until 9 months of age. The LED regimen improved survival, motor activity, muscle pathology and the autophagy cascade. A targeted lipidomic analysis of skeletal muscle and liver revealed elevations in tissue levels of non-esterified palmitic acid and ceramide (d18:1/16:0), two lipotoxic substances, in the homozygous mice. The ability to reverse lethality, increase survival, and ameliorate myopathy and lipids deficits in the VCP(R155H/R155H) homozygous animals suggests that lipid supplementation may be a promising therapeutic strategy for patients with VCP-associated neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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