Central and peripheral defects in motor units of the diaphragm of spinal muscular atrophy mice

Mol Cell Neurosci. 2016 Jan;70:30-41. doi: 10.1016/j.mcn.2015.11.007. Epub 2015 Nov 24.


Spinal muscular atrophy (SMA) is characterized by motoneuron loss and muscle weakness. However, the structural and functional deficits that lead to the impairment of the neuromuscular system remain poorly defined. By electron microscopy, we previously found that neuromuscular junctions (NMJs) and muscle fibres of the diaphragm are among the earliest affected structures in the severe mouse SMA model. Because of certain anatomical features, i.e. its thinness and its innervation from the cervical segments of the spinal cord, the diaphragm is particularly suitable to characterize both central and peripheral events. Here we show by immunohistochemistry that, at postnatal day 3, the cervical motoneurons of SMA mice receive less stimulatory synaptic inputs. Moreover, their mitochondria become less elongated which might represent an early stage of degeneration. The NMJs of the diaphragm of SMA mice show a loss of synaptic vesicles and active zones. Moreover, the partly innervated endplates lack S100 positive perisynaptic Schwann cells (PSCs). We also demonstrate the feasibility of comparing the proteomic composition between diaphragm regions enriched and poor in NMJs. By this approach we have identified two proteins that are significantly upregulated only in the NMJ-specific regions of SMA mice. These are apoptosis inducing factor 1 (AIFM1), a mitochondrial flavoprotein that initiates apoptosis in a caspase-independent pathway, and four and a half Lim domain protein 1 (FHL1), a regulator of skeletal muscle mass that has been implicated in several myopathies.

Keywords: Diaphragm; Motoneuron; Neuromuscular junction; Perisynaptic Schwann cell; Proteomics; Spinal muscular atrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Inducing Factor / metabolism
  • Diaphragm / innervation*
  • Diaphragm / metabolism
  • Diaphragm / physiopathology
  • Disease Models, Animal
  • Intracellular Signaling Peptides and Proteins / metabolism
  • LIM Domain Proteins / metabolism
  • Mice
  • Motor Neurons / metabolism*
  • Muscle Proteins / metabolism
  • Muscular Atrophy, Spinal / metabolism*
  • Muscular Atrophy, Spinal / physiopathology
  • Neuromuscular Junction / metabolism
  • Proteomics
  • Schwann Cells / metabolism
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 1 Protein / metabolism*
  • Synaptic Vesicles / metabolism


  • Apoptosis Inducing Factor
  • FHL1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Muscle Proteins
  • Pdcd8 protein, mouse
  • Survival of Motor Neuron 1 Protein