Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy

Autophagy. 2013 May;9(5):799-800. doi: 10.4161/auto.23958. Epub 2013 Feb 25.

Abstract

Pathological phenotypes in inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (IBMPFD/ALS) include defective autophagosome and endosome maturation that result in vacuolation, weakness and muscle atrophy. The link between autophagy and IBMPFD/ALS pathobiology has been poorly understood. We examined the AKT-FOXO3 and MTOR pathways to characterize the regulation of autophagy in IBMPFD/ALS mouse muscle. We identified a defect in MTOR signaling that results in enhanced autophagosome biogenesis. Modulating MTOR signaling may therefore be a viable therapeutic target in IBMPFD/ALS.

Keywords: MTOR; VCP; autophagy; myopathy; rapamycin.

MeSH terms

  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Autophagy / drug effects*
  • Cell Cycle Proteins / metabolism*
  • Disease Models, Animal
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology
  • Humans
  • Mice
  • Muscle Weakness / metabolism*
  • Muscle Weakness / pathology*
  • Mutant Proteins / metabolism
  • Myositis, Inclusion Body / metabolism*
  • Myositis, Inclusion Body / pathology*
  • Osteitis Deformans / metabolism
  • Osteitis Deformans / pathology
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism
  • Valosin Containing Protein

Substances

  • Cell Cycle Proteins
  • Mutant Proteins
  • TOR Serine-Threonine Kinases
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse
  • Sirolimus