TY - JOUR
T1 - Transgenic expression of inclusion body myopathy associated mutant p97/VCP causes weakness and ubiquitinated protein inclusions in mice
AU - Weihl, Conrad C.
AU - Miller, Sara E.
AU - Hanson, Phyllis I.
AU - Pestronk, Alan
N1 - Funding Information:
We thank Drs Virginia Kimonis and Giles Watts for thoughtful discussion regarding the construction of transgenic animals. Plasmid 1256MCK-CAT transgenic targeting vector was a kind gift from Dr Stephen Hauschka, University of Washington. We thanks Dr David Harris for help with animal husbandry. This research was supported through NIH R01NS050717 (P.I.H.) and NIH K08 AG026271 (C.C.W.).
PY - 2007/4/15
Y1 - 2007/4/15
N2 - Mutations in p97/VCP cause the autosomal-dominant, inherited syndrome inclusion body myopathy (IBM) associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD) (Watts, G.D., Wymer, J., Kovach, M.J., Mehta, S.G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M.P. and Kimonis, V.E. (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. p97/VCP is a multi-functional protein with a role in the ubiquitin-proteasome system (UPS) (Wang, Q., Song, C. and Li, C.C. (2004) Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. To understand how mutations in this protein lead to a myopathy, we generated several lines of transgenic mice expressing p97/VCP-WT (TgVCP-WT) or the most common IBMPFD mutant, p97/VCP R155H (TgVCP-RH), under a muscle-specific promoter. TgVCP-RH animals, but not controls, became progressively weaker in a dose-dependent manner starting at 6 months of age. Abnormal muscle pathology, which included coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 expression at the sarcolemma developed coincident with the onset of weakness. These changes were not associated with alterations in sarcolemmal integrity as measured by muscle fiber uptake of Evan's blue dye. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high-molecular-weight ubiquitinated proteins, markers of UPS dysfunction. We suggest that this early and persistent increase in ubiquitinated proteins induced by IBMPFD mutations in p97/VCP may ultimately lead to animal weakness and the observed muscle pathology. TgVCP-RH animals will be a valuable tool for understanding the pathogenesis of IBM and the role of the UPS in skeletal muscle.
AB - Mutations in p97/VCP cause the autosomal-dominant, inherited syndrome inclusion body myopathy (IBM) associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD) (Watts, G.D., Wymer, J., Kovach, M.J., Mehta, S.G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M.P. and Kimonis, V.E. (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. p97/VCP is a multi-functional protein with a role in the ubiquitin-proteasome system (UPS) (Wang, Q., Song, C. and Li, C.C. (2004) Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. To understand how mutations in this protein lead to a myopathy, we generated several lines of transgenic mice expressing p97/VCP-WT (TgVCP-WT) or the most common IBMPFD mutant, p97/VCP R155H (TgVCP-RH), under a muscle-specific promoter. TgVCP-RH animals, but not controls, became progressively weaker in a dose-dependent manner starting at 6 months of age. Abnormal muscle pathology, which included coarse internal architecture, vacuolation and disorganized membrane morphology with reduced caveolin-3 expression at the sarcolemma developed coincident with the onset of weakness. These changes were not associated with alterations in sarcolemmal integrity as measured by muscle fiber uptake of Evan's blue dye. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high-molecular-weight ubiquitinated proteins, markers of UPS dysfunction. We suggest that this early and persistent increase in ubiquitinated proteins induced by IBMPFD mutations in p97/VCP may ultimately lead to animal weakness and the observed muscle pathology. TgVCP-RH animals will be a valuable tool for understanding the pathogenesis of IBM and the role of the UPS in skeletal muscle.
UR - http://www.scopus.com/inward/record.url?scp=34447093377&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddm037
DO - 10.1093/hmg/ddm037
M3 - Article
C2 - 17329348
AN - SCOPUS:34447093377
VL - 16
SP - 919
EP - 928
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 8
ER -