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Activin IIB receptor blockade improves muscular function in a mouse model of spinal muscular atrophy
Author(s) -
Liu Min,
Barton Elisabeth R,
Sweeney H. Lee
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1078.1
Subject(s) - sma* , spinal muscular atrophy , neuromuscular junction , muscle atrophy , medicine , skeletal muscle , endocrinology , neuromuscular blockade , stimulation , compound muscle action potential , atrophy , hindlimb , motor neuron , biology , neuroscience , anesthesia , electrophysiology , disease , mathematics , combinatorics
Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. To determine the effects of activin Type IIB receptor (ActRIIB) blockade on muscle function in SMA, a systemic inhibition of ActRIIB signaling was performed via AAV‐mediated gene transfer of a soluble form of the extracellular domain of the ActRIIB (sActRIIB). Four‐week old male SMA mice (C/C mice: a new model for milder, possibly Type III SMA) were injected with 1E12 genome copies of AAV 2/8 LSP.sActRIIB via i.p. injection. In situ functional assessment of TA and EDL were performed at 8 weeks post injection. Synaptic efficacy of neuromuscular junction (NMJ) was assessed by comparing muscle tetanic tension between nerve and direct muscle stimulation. Treatment with ActRIIB blockade led to an increased skeletal muscle mass in all hindlimb muscles studied, with concomitant increases in peak tetanic force in both TA and EDL. However, the treated muscles showed a significant reduction in muscle specific force and the ratio of nerve/direct stimulation. This study indicates that ActRIIB blockade represents an effective therapeutic strategy to prevent muscle atrophy and enhance the muscle function in SMA, but the elevation of muscle mass may increase the loading of the motor units and/or NMJ. The long‐term consequences of this are now under investigation.