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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 4

Little cellular pathology in young adult MyoD-iCre SmnF7/– mutants bearing 2 SMN2 copies.

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Little cellular pathology in young adult MyoD-iCre SmnF7/– mutants beari...
(A) Comparisons of body weights of controls and mutants harboring 1 or 2 SMN2 copies; 1-way ANOVA, n ≥ 10 mice of each cohort. (B) Western blot results showing selective depletion of SMN protein in skeletal muscle of a P30 MyoD-iCre SMN2+/+ SmnF7/– mutant. (C) Quantified levels of SMN protein in P30 mutant and control mice; t test, n ≥ 3 mice from each group. (D) Transverse sections of H&E-stained gastrocnemius muscles from a P30 mutant and control did not reveal major morphological differences between the two. Scale bar: 25 μm. Graphs of (E) myofiber areas, (F) fibers containing central nuclei, and (G) serum creatine kinase (CK) levels in young mutants and controls. NS: P > 0.05, t test, n > 150 fibers from n = 3 mice from each group for results in E and F; NS: P > 0.05, t test, n = 10 mice for CK values. (H) NMJs from the triceps of a P30 mutant and a control showing similar morphology of pre- and postsynaptic compartments in the 2 mice. Scale bar: 30 μm. (I) Graph of the extent of NMJ innervation in P30 mutants and controls. (J) Graph depicting endplate complexity in P30 mutants and control littermates. NS: P > 0.05, Fisher’s exact test, n ≥ 300 NMJs from n = 3 mice from each group of mice for analyses in I and J. **P < 0.01; ***P < 0.001.

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

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