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

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 8

SMN repletion mitigates muscle defects in symptomatic mutants.

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SMN repletion mitigates muscle defects in symptomatic mutants. Levels of...
Levels of the (A) SMN2-derived FL-SMN transcripts and (B) SMN protein in gastrocnemius muscles of controls and mutants either administered an SMN2 splice-switching MO or a nonspecific MO at 7 months of age; 1-way ANOVA, n = 3 mice of each genotype. (C) Western blot probed for SMN protein in skeletal muscle after treatment with SMN-MO or scrambled MO. (D) Muscle weights in mice treated as described in the previous panels; 1-way ANOVA, n ≥ 3 mice in each group. (E) Transverse sections of gastrocnemius muscles from treated mutants and controls. Less pathology in the form of central nuclei (arrowheads), hypotrophic fibers (open arrows), and degenerating fibers (solid arrows) observed in SMN-MO treated muscle. Scale bar: 100 μm. Quantified results of (F) central nuclei and (G) myofiber areas in muscles from the mice; 1-way ANOVA, n ≥ 300 fibers from n ≥ 3 mice of each cohort. (H) Endplates from the 3 sets of mice; fewer fragmented NMJs are seen in the SMN-MO treated mutant than in its counterpart administered scrambled MO. Scale bar: 25 μm. (I) NMJ area measurements and (J) NMJ complexity analysis in gastrocnemius muscles of treated mutants or littermate controls; 1-way ANOVA, n ≥ 400 endplates from n ≥ 3 mice of each genotype for results in I and J. *P < 0.05; **P < 0.01; ***P < 0.001.