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mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion

James K Ching1, Sarita V Elizabeth, Jeong-Sun Ju

  • 1Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO 63110, USA.

Human Molecular Genetics
|December 20, 2012
PubMed

Insights

Valosin-containing protein (VCP) mutations disrupt muscle autophagy and mTOR signaling, worsening inclusion body myopathy (IBM). Inhibiting mTOR with rapamycin exacerbates VCP-IBM symptoms, suggesting caution in treating autophagic disorders.

Area of Science:

  • Cellular Biology
  • Neuroscience
  • Muscle Physiology

Background:

  • Autophagy is crucial for cellular health and is impaired in degenerative myopathies.
  • Mutations in valosin-containing protein (VCP) cause IBMPFD/ALS, a disease affecting muscles, bone, and brain.
  • VCP is vital for protein degradation pathways, and its mutations disrupt cellular homeostasis.

Purpose of the Study:

  • To investigate the regulation of autophagy in VCP-mutant inclusion body myopathy (IBM) muscle.
  • To elucidate the role of the AKT/FOXO3 and mammalian target of rapamycin (mTOR) pathways in VCP-IBM pathogenesis.
  • To determine the impact of mTOR signaling on disease progression and potential therapeutic strategies.

Main Methods:

  • Analysis of AKT/FOXO3 and mTOR pathway signaling in VCP-IBM muscle.
  • Assessment of protein translation, autophagosome biogenesis, and autophagic substrate accumulation.
  • In vivo studies using VCP-IBM mouse models treated with rapamycin, insulin, amino acids, and Rheb activators.

Main Results:

  • VCP-IBM muscle exhibits decreased mTOR signaling, diminished protein translation, and increased autophagosome biogenesis.
  • Rapamycin treatment worsened muscle weakness, atrophy, and vacuolation in VCP-IBM mice, with increased autophagic substrate accumulation.
  • mTOR signaling could be partially rescued by insulin and amino acid stimulation; Rheb activation improved muscle fiber size.

Conclusions:

  • VCP mutations disrupt mTOR signaling, contributing to the pathogenesis of IBMPFD/ALS.
  • Targeting mTOR with inhibitors like rapamycin may exacerbate VCP-IBM and related autophagic disorders.
  • Understanding VCP's role in mTOR regulation offers insights into potential therapeutic interventions for myopathies.

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