Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models

J Clin Invest. 2020 Mar 2;130(3):1271-1287. doi: 10.1172/JCI131989.


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.

Keywords: Neuromuscular disease; Neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Atrophy, Spinal / drug therapy
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / metabolism*
  • Muscular Atrophy, Spinal / pathology
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 1 Protein / metabolism*


  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein