Abstract
Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.
Highlights
Inclusion body myopathy (IBM) associated with Paget’s disease of the bone (PDB) and Frontotemporal Dementia, (IBMPFD, MIM 167320), was first reported in 2000 by Kimonis et al [1] and mapped to the human chromosomal region 9p13.3–12 [2], [3]
We investigated the effects of rapamycin and chloroquine administration in 18–20 month old VCPR155H/+ heterozygous and Wild Type (WT) mice to assess any potential therapeutic value for patients with Valosin-Containing Protein (VCP) multisystem proteinopathy
To determine the effects of rapamycin in vivo, VCPR155H/+ and WT animals (n = 10/group) were treated with rapamycin (i.p.) at 3mg/kg/ body weight and followed over a period of 8 weeks where Rotarod performance measurements were obtained at 2-week intervals
Summary
Inclusion body myopathy (IBM) associated with Paget’s disease of the bone (PDB) and Frontotemporal Dementia, (IBMPFD, MIM 167320), was first reported in 2000 by Kimonis et al [1] and mapped to the human chromosomal region 9p13.3–12 [2], [3]. Classic symptoms of VCP disease include weakness and atrophy of the skeletal muscles of the pelvic and shoulder girdle muscles in 90% of individuals [1,2,3]. The variable phenotype is often diagnosed as limb girdle muscular dystrophy, amyotrophic lateral sclerosis (ALS), facioscapular muscular dystrophy, or scapuloperoneal muscular dystrophy [5, 7, 8]. Fifteen percent of individuals with hereditary inclusion body myopathy have an ALS-like phenotype and VCP mutations have been noted in 2–3% of isolated familial amyotrophic lateral sclerosis (fALS) cases [5, 22]
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