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Muscle-specific SMN reduction reveals motor neuron–independent disease in spinal muscular atrophy models
Jeong-Ki Kim, … , Chien-Ping Ko, Umrao R. Monani
Jeong-Ki Kim, … , Chien-Ping Ko, Umrao R. Monani
Published February 10, 2020
Citation Information: J Clin Invest. 2020;130(3):1271-1287. https://doi.org/10.1172/JCI131989.
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Research Article Neuroscience

Muscle-specific SMN reduction reveals motor neuron–independent disease in spinal muscular atrophy models

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Abstract

Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis associated with the disease derives solely from dysfunctional motor neurons that may be efficiently targeted by restricted delivery of SMN-enhancing agents to the nervous system, or stems from broader defects of the motor unit, arguing for systemic SMN repletion. We investigated the disease-contributing effects of low SMN in one relevant peripheral organ — skeletal muscle — by selectively depleting the protein in only this tissue. We found that muscle deprived of SMN was profoundly damaged. Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, neuromuscular junction abnormalities, compromised motor performance, and premature death. Importantly, restoring SMN after the onset of muscle pathology reversed disease. Our results provide the most compelling evidence yet for a direct contributing role of muscle in SMA and argue that an optimal therapy for the disease must be designed to treat this aspect of the dysfunctional motor unit.

Authors

Jeong-Ki Kim, Narendra N. Jha, Zhihua Feng, Michelle R. Faleiro, Claudia A. Chiriboga, Lan Wei-Lapierre, Robert T. Dirksen, Chien-Ping Ko, Umrao R. Monani

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Figure 2

Severe, early-onset disease in MyoD-iCre SmnF7/– mutants bearing 1 SMN2 copy.

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Severe, early-onset disease in MyoD-iCre SmnF7/– mutants bearing 1 SMN2 ...
(A) Graph depicts reduced weight of mutants; t test, n ≥ 10 mice of each set. (B) A typical mutant and control littermate reflecting the smaller size of the former. (C) Mutants perform poorly in a righting reflex test; t test, n ≥ 10 mice of each cohort. (D) Kaplan-Meier survival curves depict reduced lifespan of mutants. P < 0.0001 between groups, log-rank test, n = 25 mice from each group. (E) Western blot showed reduced SMN protein in skeletal muscle of a MyoD-iCre SMN2+/– SmnF7/– mutant. (F) Relative SMN levels in skeletal muscle of the mutants and relevant controls; 1-way ANOVA, n ≥ 3 mice of each cohort. (G) Limb and respiratory muscle fibers are markedly reduced in size in P15 mutants; t test, n ≥ 600 fibers from n = 3 mice of each cohort. (H) H&E-stained transverse sections of intercostal muscles from a P15 mutant and control showing tissue loss, and fibers with central nuclei (arrows) in the former. Scale bar: 20 μm. Quantification of (I) central nuclei and (J) fiber numbers in intercostal muscle of P15 mutants and controls. t test, n = 3–5 mice from each group. *P < 0.05; **P < 0.01; ***P < 0.001 for all analyses.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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