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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 7

NMJ pathology and neuromuscular dysfunction in MyoD-iCre SmnF7/– mutants bearing 2 SMN2 copies.

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NMJ pathology and neuromuscular dysfunction in MyoD-iCre SmnF7/– mutants...
(A) NMJs from the EDL muscles of 7-month-old mice show profound fragmentation of endplates in mutants. Scale bar: 10 μm. (B) Quantified representation of fragmented NMJs in 7-month-old mutant and control mice; t test, n ≥ 500 endplates from n ≥ 3 mice of each genotype. (C) Graph depicts NMJ size in gastrocnemius muscles of 7-month-old mutants and controls; t test, n ≥ 420 endplates from n = 3 mice of each genotype. Quantified depictions of (D) MEPP amplitude, (E) MEPP frequency, (F) EPP amplitude, and (G) quantal content in EDL muscles of 7-month-old mutant and control mice. NS: P > 0.05, t test, n ≥ 10 endplates per animal from n ≥ 4 mice of each genotype. Graphs represent (H) myofiber numbers and (I) the proportion of fibers with central nuclei in EDL muscles of analyzed mice; t test, n ≥ 4 mice of each genotype. Quantified depictions of (J) peak specific force, (K) relative force drop, and (L) rate of maximal force production in soleus muscles of 5- to 7-month-old mice; 2-way ANOVA for results in J and t tests for results in K and L, n ≥ 5 mice of each cohort. *P < 0.05; **P < 0.01; ***P < 0.001.
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