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Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy.
PLoS One. 2016; 11(11):e0166803.Plos

Abstract

Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA.

Authors+Show Affiliations

Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida, United States of America. Myology Institute, University of Florida College of Medicine, Gainesville, Florida, United States of America.Myology Institute, University of Florida College of Medicine, Gainesville, Florida, United States of America. Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, Florida, United States of America.Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. Department of Pharmacology & Therapeutics, University of Florida College of Medicine, Gainesville, Florida, United States of America. Myology Institute, University of Florida College of Medicine, Gainesville, Florida, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27870893

Citation

Liu, Min, et al. "Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy." PloS One, vol. 11, no. 11, 2016, pp. e0166803.
Liu M, Hammers DW, Barton ER, et al. Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy. PLoS ONE. 2016;11(11):e0166803.
Liu, M., Hammers, D. W., Barton, E. R., & Sweeney, H. L. (2016). Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy. PloS One, 11(11), e0166803. https://doi.org/10.1371/journal.pone.0166803
Liu M, et al. Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy. PLoS ONE. 2016;11(11):e0166803. PubMed PMID: 27870893.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy. AU - Liu,Min, AU - Hammers,David W, AU - Barton,Elisabeth R, AU - Sweeney,H Lee, Y1 - 2016/11/21/ PY - 2016/08/02/received PY - 2016/11/03/accepted PY - 2016/11/22/entrez PY - 2016/11/22/pubmed PY - 2017/6/27/medline SP - e0166803 EP - e0166803 JF - PloS one JO - PLoS ONE VL - 11 IS - 11 N2 - Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/27870893/Activin_Receptor_Type_IIB_Inhibition_Improves_Muscle_Phenotype_and_Function_in_a_Mouse_Model_of_Spinal_Muscular_Atrophy_ L2 - http://dx.plos.org/10.1371/journal.pone.0166803 DB - PRIME DP - Unbound Medicine ER -