Abstract
The discovery of effective therapies and of disease mechanisms underlying valosin containing protein (VCP)-associated myopathies and neurodegenerative disorders remains elusive. VCP disease, caused by mutations in the VCP gene, are a clinically and genetically heterogeneous group of disorders with manifestations varying from hereditary inclusion body myopathy, Paget’s disease of bone, frontotemporal dementia (IBMPFD), and amyotrophic lateral sclerosis (ALS). In the present study, we examined the effects of higher dietary lipid percentages on VCPR155H/R155H, VCPR155H/+ and Wild Type (WT) mice from birth until 15 months of age by immunohistochemical and biochemical assays. Findings illustrated improvement in the muscle strength, histology, and autophagy signaling pathway in the heterozygote mice when fed 9% lipid-enriched diets (LED). However, increasing the LED by 12%, 30%, and 48% showed no improvement in homozygote and heterozygote survival, muscle pathology, lipid accumulation or the autophagy cascade. These findings suggest that a balanced lipid supplementation may have a therapeutic strategy for patients with VCP-associated multisystem proteinopathies.
Highlights
Inclusion body myopathy associated with Paget’s disease of bone, and frontotemporal dementia (IBMPFD), more recently termed multisystem proteinopathy (MSP), is a progressive, fatal genetic disorder caused by mutations in the valosin containing protein (VCP) gene [1]
Western blot analyses of ubiquitin and LC3-I/II expression levels showed no significant changes in Wild Type (WT) and VCPR155H/+ on a 9% lipid-enriched diets (LED) vs. normal diet (ND) starting at 7 months of age (p > 0.05, Fig 1E)
Several studies have previously demonstrated that high fat diets (HFDs) provide powerful therapeutic platforms for many diverse neurological disorders including Alzheimer’s disease (AD), Parkinson disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and epilepsies [25,26,27,28,29,30]
Summary
Inclusion body myopathy associated with Paget’s disease of bone, and frontotemporal dementia (IBMPFD), more recently termed multisystem proteinopathy (MSP), is a progressive, fatal genetic disorder caused by mutations in the VCP gene [1]. Affected individuals exhibit scapular winging and progressive muscle weakness and die from cardiac and respiratory failures [1,2,3,4]. Myopathy is the most common feature, present in nearly ninety percent of affected individuals with patients typically depicting weakness and atrophy of skeletal, PLOS ONE | DOI:10.1371/journal.pone.0131995. Rimmed vacuoles and TAR DNA Binding Protein-43 (TDP-43)-positive ubiquitinated inclusion bodies are hallmarks in IBMPFD patients’ muscles [2, 5, 6, 7]
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