Mitofusin 2 Regulates Axonal Transport of Calpastatin to Prevent Neuromuscular Synaptic Elimination in Skeletal Muscles

Cell Metab. 2018 Sep 4;28(3):400-414.e8. doi: 10.1016/j.cmet.2018.06.011. Epub 2018 Jul 12.


Skeletal muscles undergo atrophy in response to diseases and aging. Here we report that mitofusin 2 (Mfn2) acts as a dominant suppressor of neuromuscular synaptic loss to preserve skeletal muscles. Mfn2 is reduced in spinal cords of transgenic SOD1G93A and aged mice. Through preserving neuromuscular synapses, increasing neuronal Mfn2 prevents skeletal muscle wasting in both SOD1G93A and aged mice, whereas deletion of neuronal Mfn2 produces neuromuscular synaptic dysfunction and skeletal muscle atrophy. Neuromuscular synaptic loss after sciatic nerve transection can also be alleviated by Mfn2. Mfn2 coexists with calpastatin largely in mitochondria-associated membranes (MAMs) to regulate its axonal transport. Genetic inactivation of calpastatin abolishes Mfn2-mediated protection of neuromuscular synapses. Our results suggest that, as a potential key component of a novel and heretofore unrecognized mechanism of cytoplasmic protein transport, Mfn2 may play a general role in preserving neuromuscular synapses and serve as a common therapeutic target for skeletal muscle atrophy.

Keywords: Mfn2; amyotrophic lateral sclerosis; axonal transport; calpastatin; mitochondria; mitochondria-associated membranes; nerve injury; neuromuscular synapse; sarcopenia; skeletal muscle atrophy.

Publication types

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

MeSH terms

  • Aging / metabolism*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Axonal Transport / physiology*
  • Calcium-Binding Proteins / metabolism*
  • Disease Models, Animal
  • GTP Phosphohydrolases / physiology*
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondrial Proteins / metabolism
  • Muscle, Skeletal* / innervation
  • Muscle, Skeletal* / metabolism
  • Muscular Atrophy / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Synapses
  • Synaptic Transmission / physiology*


  • Calcium-Binding Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • calpastatin
  • GTP Phosphohydrolases
  • Mfn2 protein, mouse