Abstract
Dominant mutations in the valosin containing protein (VCP) gene cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia (IBMPFD). We have generated a knock-in mouse model with the common R155H mutation. Mice demonstrate progressive muscle weakness starting approximately at the age of 6 months. Histology of mutant muscle showed progressive vacuolization of myofibrils and centrally located nuclei, and immunostaining shows progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in quadriceps myofibrils and brain. Increased LC3-II staining of muscle sections representing increased number of autophagosomes suggested impaired autophagy. Increased apoptosis was demonstrated by elevated caspase-3 activity and increased TUNEL-positive nuclei. X-ray microtomography (uCT) images show radiolucency of distal femurs and proximal tibiae in knock-in mice and uCT morphometrics shows decreased trabecular pattern and increased cortical wall thickness. Bone histology and bone marrow derived macrophage cultures in these mice revealed increased osteoclastogenesis observed by TRAP staining suggestive of Paget bone disease. The VCPR155H/+ knock-in mice replicate the muscle, bone and brain pathology of inclusion body myopathy, thus representing a useful model for preclinical studies.
Highlights
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) is characterized by progressive muscle weakness, bone deformities and extensive neuro-degeneration [1]
Generation of VCPR155H/+ knock-in mice To generate a mouse model for human IBMPFD disease, we created knock-in mice that are heterozygous for the most common valosin containing protein (VCP) disease mutation R155H through a Neo cassette insertion using 129/SvEv mice (Figure 1A). These mice were back-crossed more than six times with C57BL/6 strain before experiments were done to make sure that the majority (.98%) of the genetic background of generated mice was of C57BL/6 origin
Old) of mutant cells had inclusion bodies that were positive for the TAR DNA binding protein-43 (TDP-43) and ubiquitin-specific antibodies, versus 2.1% in 15-month old control mice, (Figure 4 and Table 1)
Summary
Inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD, OMIM 167320) is characterized by progressive muscle weakness, bone deformities and extensive neuro-degeneration [1]. Disease progression is characterized by generalized muscle weakness resulting in respiratory and cardiac failure in the later stages [5]. The diagnosis of IBMPFD muscle disease is based on skeletal muscle weakness, and the presence of rimmed vacuoles and inclusion bodies in the muscle [1,6,7]. These inclusions have been shown to be positive for the TAR DNA binding protein-43 (TDP-43) and ubiquitin antibodies [8]. Studies in patient myoblasts have revealed vacuoles and increased LC3 and autophagosome formation suggestive of impaired autophagy [9]
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