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

Luwen Wang, Ju Gao, Jingyi Liu, Sandra L. Siedlak, Sandy Torres, Hisashi Fujioka, Mikayla L. Huntley, Yinfei Jiang, Haiyan Ji, Tingxiang Yan, Micah Harland, Pichet Termsarasab, Sophia Zeng, Zhen Jiang, Jingjing Liang, George Perry, Charles Hoppel, Cheng Zhang, Hu Li, Xinglong Wang

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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. Wang et al. report on the unexpected function of the mitochondrial outer membrane protein mitofusin 2 (Mfn2) in mediating the axonal transport of calpastatin, which is involved in neuromuscular function, to protect neuromuscular synapses. Mfn2 overexpression can prevent neuromuscular synapse loss in amyotrophic lateral sclerosis (ALS) and aging-related sarcopenia.

Original languageEnglish (US)
Pages (from-to)400-414.e8
JournalCell Metabolism
Volume28
Issue number3
DOIs
StatePublished - Sep 4 2018

Keywords

  • Mfn2
  • amyotrophic lateral sclerosis
  • axonal transport
  • calpastatin
  • mitochondria
  • mitochondria-associated membranes
  • nerve injury
  • neuromuscular synapse
  • sarcopenia
  • skeletal muscle atrophy

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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