Our recent microarray studies in muscle indicate that multiple signaling pathways are dysregulated in patients with VCP-associated inclusion body myopathy, which include abnormalities in the actin cytoskeleton, ErbB signaling, cancer, regulation of autophagy and lysosomal signaling transduction cascades ( 8). Mutations in VCP are primarily within the N-terminal domain, which is involved in ubiquitin binding and protein–protein interactions. VCP, a member of the type II AAA+ ATPase family, plays important roles in a plethora of cellular activities. The R155H mutation is by far the most common, accounting for∼50% of affected individuals. VCP disease is increasingly being recognized, with >31 VCP mutations having been identified worldwide. Variable phenotypes include limb girdle muscular dystrophy (LGMD) or amyotrophic lateral sclerosis (ALS).

Histologically, patients display rimmed vacuoles and TAR DNA-Binding Protein-43 (TDP-43)-positive, ubiquitinated inclusion bodies in muscles ( 1, 5– 7). Affected individuals exhibit scapular winging, progressive muscle weakness and die from cardiac and respiratory failure ( 1, 5). Hereditary inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia (IBMPFD) caused by mutations in the VCP gene is associated with weakness and atrophy of skeletal, pelvic and shoulder girdle muscles in 90% of individuals ( 1– 4). The ability to reverse lethality, increase survival, and ameliorate myopathy and lipids deficits in the VCP R155H/R155H homozygous animals suggests that lipid supplementation may be a promising therapeutic strategy for patients with VCP-associated neurodegenerative diseases. A targeted lipidomic analysis of skeletal muscle and liver revealed elevations in tissue levels of non-esterified palmitic acid and ceramide (d18:1/16:0), two lipotoxic substances, in the homozygous mice. The LED regimen improved survival, motor activity, muscle pathology and the autophagy cascade. We examined the effects of this diet on homozygous and wild-type mice from birth until 9 months of age. Herein, we report that feeding pregnant VCP R155H/+ heterozygous dams with a lipid-enriched diet (LED) results in the reversal of the lethal phenotype in VCP R155H/R155H homozygous offspring. In our previous investigation, VCP R155H/R155H homozygous mice exhibited progressive weakness and accelerated pathology prior to their early demise. VCP mouse models carrying the common R155H mutation include several of the features typical of the human disease.

Currently, there are no effective treatments for VCP myopathy or dementia. Valosin-containing protein (VCP)-associated disease caused by mutations in the VCP gene includes combinations of a phenotypically heterogeneous group of disorders such as hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis.

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