Inclusion body myopathies (IBM) are disabling skeletal muscle disorders and considered a prototypical age related muscle disease. There is no effective treatment. IBM muscle has characteristic "rimmed vacuoles" and eosinophilic inclusions. These structures contain ubiquitinated and undegraded insoluble proteins that include ss-amyloid and phosphorylated tau; proteins that accumulate in Alzheimer's Disease brains. This overlapping pathology suggests a common pathogenic mechanism between IBM and neurodegenerative disorders. This link is strengthened further by the identification of mutations in the protein p97/VCP that cause the autosomal dominant syndrome, IBMPFD, IBM associated with paget's disease of the bone and frontotemporal dementia (FTD). p97/VCP is essential for the degradation of cytosolic derived proteasome substrates as well as for endoplasmic reticulum associated degradation of misfolded secreted or transmembrane proteins. It performs this role by selectively binding with ubiquitinated substrates via co-factors and transferring them to the 26S proteasome machinery. Currently it is unclear how mutations in p97/VCP cause disease. IBMPFD brain and muscle contains ubiquitinated protein inclusions. Our studies demonstrate that IBMPFD mutant p97/VCP leads to an increase in ubiquitinated proteins in cells. Skeletal muscle expression of IBMPFD mutant p97/VCP in mice causes an increase in ubiquitinated proteins as early as 30 days of life before weakness and myopathic changes which occur after 6 months of age. We propose to (1) study the biochemical properties of IBMPFD mutant p97/VCP with regard to structure, enzymatic activity and substrate binding. We will also (2) evaluate the effect of IBMPFD mutant p97/VCP on the ubiquitin-proteasome system (UPS) in cell culture and transgenic animals. These studies will use in vivo bioluminescent imaging of UPS function in skeletal muscle from living animals. Finally (3) we will compare the results obtained above with two complementary loss of p97/VCP function models. Although a rare disorder, the study of IBMPFD is essential to understand the role of the UPS in normal aging and aging related disorders such as sIBM and FTD.

Public Health Relevance

IBMPFD is an aging related multi-system disorder with both muscle weakness and dementia, due to mutations in the ubiquitin proteasome system (UPS) essential protein p97/VCP. We propose to explore the consequence of disease mutations in p97/VCP on UPS-mediated protein degradation in skeletal muscle and its relevance to aging related disorders such as inclusion body myositis and fronto-temporal dementia.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Velazquez, Jose M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Meyer, Hemmo; Weihl, Conrad C (2014) The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci 127:3877-83
Chou, Tsui-Fen; Bulfer, Stacie L; Weihl, Conrad C et al. (2014) Specific inhibition of p97/VCP ATPase and kinetic analysis demonstrate interaction between D1 and D2 ATPase domains. J Mol Biol 426:2886-99
Stein, Kevin C; Bengoechea, Rocio; Harms, Matthew B et al. (2014) Myopathy-causing mutations in an HSP40 chaperone disrupt processing of specific client conformers. J Biol Chem 289:21120-30
Gonzalez, Michael A; Feely, Shawna M; Speziani, Fiorella et al. (2014) A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease. Brain 137:2897-902
Bibee, Kristin P; Cheng, Ya-Jian; Ching, James K et al. (2014) Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. FASEB J 28:2047-61
Udan-Johns, Maria; Bengoechea, Rocio; Bell, Shaughn et al. (2014) Prion-like nuclear aggregation of TDP-43 during heat shock is regulated by HSP40/70 chaperones. Hum Mol Genet 23:157-70
Weihl, Conrad C (2013) Monitoring autophagy in the treatment of protein aggregate diseases: steps toward identifying autophagic biomarkers. Neurotherapeutics 10:383-90
Ching, James K; Weihl, Conrad C (2013) Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. Autophagy 9:799-800
Ching, James K; Elizabeth, Sarita V; Ju, Jeong-Sun et al. (2013) mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet 22:1167-79
Benatar, Michael; Wuu, Joanne; Fernandez, Catalina et al. (2013) Motor neuron involvement in multisystem proteinopathy: implications for ALS. Neurology 80:1874-80

Showing the most recent 10 out of 27 publications