Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice
| Autor: | Louis J. Dell'Italia, Antanina Voit, Vishwendra Patel, Dongsheng Duan, Joseph J. McArdle, Ronald Pachon, Lai-Hua Xie, Erik Kohlbrenner, Jerry R. Mendell, Gopal J. Babu, Mohammad Bakhutma, Vikas Shah, Diego Fraidenraich, Roger J. Hajjar |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
musculoskeletal diseases medicine.medical_specialty SERCA Utrophin Duchenne muscular dystrophy Science Proteolipids Cardiomyopathy General Physics and Astronomy Muscle Proteins General Biochemistry Genetics and Molecular Biology Article Sarcoplasmic Reticulum Calcium-Transporting ATPases Dystrophin 03 medical and health sciences Mice Internal medicine medicine Animals Gene Silencing Muscular dystrophy lcsh:Science Mice Knockout Multidisciplinary biology business.industry Skeletal muscle General Chemistry Genetic Therapy medicine.disease 3. Good health Sarcolipin Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure Gene Expression Regulation biology.protein Mice Inbred mdx lcsh:Q RNA Interference business Cardiomyopathies |
| Zdroj: | Nature Communications Nature Communications, Vol 8, Iss 1, Pp 1-14 (2017) |
| ISSN: | 2041-1723 |
| Popis: | Sarcolipin (SLN) is an inhibitor of the sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) and is abnormally elevated in the muscle of Duchenne muscular dystrophy (DMD) patients and animal models. Here we show that reducing SLN levels ameliorates dystrophic pathology in the severe dystrophin/utrophin double mutant (mdx:utr −/−) mouse model of DMD. Germline inactivation of one allele of the SLN gene normalizes SLN expression, restores SERCA function, mitigates skeletal muscle and cardiac pathology, improves muscle regeneration, and extends the lifespan. To translate our findings into a therapeutic strategy, we knock down SLN expression in 1-month old mdx:utr −/− mice via adeno-associated virus (AAV) 9-mediated RNA interference. The AAV treatment markedly reduces SLN expression, attenuates muscle pathology and improves diaphragm, skeletal muscle and cardiac function. Taken together, our findings suggest that SLN reduction is a promising therapeutic approach for DMD. Sarcolipin is an inhibitor of the ATP dependent calcium pump SERCA, and is abnormally elevated in Duchenne muscular dystrophy. The authors show that reducing sarcolipin expression ameliorates skeletal muscle pathology and cardiomyopathy and extends life span in mouse models of DMD. |
| Databáze: | OpenAIRE |
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