Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice

Antanina Voit; Vishwendra Patel; Ronald Pachon; Vikas Shah; Mohammad Bakhutma; Erik Kohlbrenner; Joseph J. McArdle; Louis J. Dell'Italia; Jerry R. Mendell; Lai Hua Xie; Roger J. Hajjar; Dongsheng Duan; Diego Fraidenraich; Gopal J. Babu

doi:10.1038/s41467-017-01146-7

Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice

Antanina Voit, Vishwendra Patel, Ronald Pachon, Vikas Shah, Mohammad Bakhutma, Erik Kohlbrenner, Joseph J. McArdle, Louis J. Dell'Italia, Jerry R. Mendell, Lai Hua Xie, Roger J. Hajjar, Dongsheng Duan, Diego Fraidenraich, Gopal J. Babu

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66 Scopus citations

Abstract

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.

Original language	English (US)
Article number	1068
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01146-7
State	Published - Dec 1 2017

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-017-01146-7

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Voit, A., Patel, V., Pachon, R., Shah, V., Bakhutma, M., Kohlbrenner, E., McArdle, J. J., Dell'Italia, L. J., Mendell, J. R., Xie, L. H., Hajjar, R. J., Duan, D., Fraidenraich, D., & Babu, G. J. (2017). Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice. Nature communications, 8(1), Article 1068. https://doi.org/10.1038/s41467-017-01146-7

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title = "Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice",

abstract = "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.",

author = "Antanina Voit and Vishwendra Patel and Ronald Pachon and Vikas Shah and Mohammad Bakhutma and Erik Kohlbrenner and McArdle, {Joseph J.} and Dell'Italia, {Louis J.} and Mendell, {Jerry R.} and Xie, {Lai Hua} and Hajjar, {Roger J.} and Dongsheng Duan and Diego Fraidenraich and Babu, {Gopal J.}",

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doi = "10.1038/s41467-017-01146-7",

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Voit, A, Patel, V, Pachon, R, Shah, V, Bakhutma, M, Kohlbrenner, E, McArdle, JJ, Dell'Italia, LJ, Mendell, JR, Xie, LH, Hajjar, RJ, Duan, D, Fraidenraich, D & Babu, GJ 2017, 'Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice', Nature communications, vol. 8, no. 1, 1068. https://doi.org/10.1038/s41467-017-01146-7

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T1 - Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice

AU - Voit, Antanina

AU - Patel, Vishwendra

AU - Pachon, Ronald

AU - Shah, Vikas

AU - Bakhutma, Mohammad

AU - Kohlbrenner, Erik

AU - McArdle, Joseph J.

AU - Dell'Italia, Louis J.

AU - Mendell, Jerry R.

AU - Xie, Lai Hua

AU - Hajjar, Roger J.

AU - Duan, Dongsheng

AU - Fraidenraich, Diego

AU - Babu, Gopal J.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice

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