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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 1

Robust, muscle-specific inactivation of the SmnF7 allele with MyoD-iCre.

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Robust, muscle-specific inactivation of the SmnF7 allele with MyoD-iCre....
(A) PCR analysis of genomic DNA from tissue of mice harboring the SmnF7 allele and either MyoD-iCre or Myf5-Cre. The inactivated SmnΔ7 allele is only detected in muscle of the MyoD-iCre mice, whereas it is seen in ectopic locations of Myf5-Cre transgenics. (B) Q-PCR data comparing the efficiency of SmnF7 inactivation in muscle of mice with either MyoD-iCre or Myf5-Cre driver. **P < 0.01, t test, n ≥ 4 mice of each cohort. (C) Kaplan-Meier survival curves of Myf5-Cre SmnF7/– and MyoD-iCre SmnF7/– mice. P < 0.01 between groups, log-rank test.

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

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