title: Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice.
abstract: There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-beta family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn(-/-)) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA.
authors.affiliation: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. csumner1@jhmi.edu
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
authors.forename: Claribel D
authors.initials: CD
authors.lastname: Wee
authors.forename: Leigh C
authors.initials: LC
authors.lastname: Warsing
authors.forename: Dong W
authors.initials: DW
authors.lastname: Choe
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Ng
authors.forename: Cathleen
authors.initials: C
authors.lastname: Lutz
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Wagner
mesh_terms: D030301:Activin Receptors, Type II / Q000008:administration & dosage; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D038681:Follistatin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D055435:Myostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D038681:Follistatin; D055435:Myostatin; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B