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 6

Late-onset disease in MyoD-iCre SmnF7/– mutants bearing 2 SMN2 copies.

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Late-onset disease in MyoD-iCre SmnF7/– mutants bearing 2 SMN2 copies. R...
Results of (A) rotarod and (B) grip strength tests demonstrated the late-onset, disease-causing effects of selectively depleting SMN in skeletal muscle; t test, n ≥ 25 mice of each genotype. (C) Kaplan-Meier survival curves depict reduced lifespan of mutants. P < 0.0001 between mutants and the 2 sets of controls; P > 0.05 between the 2 sets of controls, log-rank test. (D) Transverse sections from 6- to 7-month-old mutant and control gastrocnemius muscles illustrate the presence of pathology in mutants. Hypotrophic fibers (solid arrows), regenerating fibers with cytoplasmic basophilia (open arrowhead), split fibers (solid arrowheads), or degenerating fibers (open arrows) are shown. Scale bar: 25 μm. Graphs represent (E) fiber sizes and (F) fiber numbers in muscles from 7-month-old mutants and controls; t test, n ≥ 500 fibers from n ≥ 3 mice of each genotype. (G) Estimates of central nuclei in muscles of 7-month-old mutants or controls; t test, n ≥ 1000 fibers from n ≥ 3 mice of each genotype. (H) Transverse sections of gastrocnemius muscles from 7-month-old mutant and control mice depicting damaged IgG-positive myofibers (arrows). Scale bar: 50 μm. (I) Quantification of damaged fibers from the previous experiment; t test, n ≥ 300 fibers from n ≥ 3 mice of each genotype. (J) Quantified results of serum CK values from 7-month-old mutant and control mice; t test, n ≥ 8 mice of each cohort. *P < 0.05; **P < 0.01; ***P < 0.001.