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

Abstract

Autophagy is dysfunctional in many degenerative diseases including myopathies. Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM) associated with Paget's disease of the bone, fronto-temporal dementia and amyotrophic lateral sclerosis (IBMPFD/ALS). VCP is necessary for protein degradation via the proteasome and lysosome. IBMPFD/ALS mutations in VCP disrupt autophagosome and endosome maturation resulting in vacuolation, weakness and muscle atrophy. To understand the regulation of autophagy in VCP-IBM muscle, we examined the AKT/FOXO3 and mammalian target of rapamycin (mTOR) pathways. Basal Akt and FOXO3 phosphorylation was normal. In contrast, the phosphorylation of mTOR targets was decreased. Consistent with this, global protein translation was diminished and autophagosome biogenesis was increased in VCP-IBM muscle. Further mTORC1 inhibition with rapamycin hastened weakness, atrophy and vacuolation in VCP-IBM mice. This was accompanied by the accumulation of autophagic substrates such as p62, LC3II and ubiquitinated proteins. The decrease in mTOR signaling was partially rescued by insulin and to a lesser extent by amino acid (AA) stimulation in VCP-IBM muscle. Cells expressing catalytically inactive VCP or treated with a VCP inhibitor also failed to activate mTOR upon nutrient stimulation. Expression of a constitutively active Rheb enhanced mTOR activity and increased the fiber size in VCP-IBM mouse skeletal muscle. These studies suggest that VCP mutations may disrupt mTOR signaling and contribute to IBMPFD/ALS disease pathogenesis. Treatment of some autophagic disorders with mTOR inhibitors such as rapamycin may worsen disease.

• Authors: James K Ching, Sarita V Elizabeth, Jeong-Sun Ju, Caleb Lusk, Sara K Pittman, Conrad C Weihl
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 6 Pg. 1167-79 (Mar 15 2013) ISSN: 1460-2083 [Electronic] England
• PMID: 23250913 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adenosine Triphosphatases (genetics, metabolism)
• Animals
• Autophagy
• Cell Cycle Proteins (genetics, metabolism)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myositis, Inclusion Body (genetics, metabolism, pathology, physiopathology)
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Vacuoles (metabolism, pathology)
• Valosin Containing Protein