Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease.

Mutations in valosin-containing protein (VCP) cause inclusion body myopathy (IBM), Paget's disease of the bone, and frontotemporal dementia (IBMPFD). Patient muscle has degenerating fibers, rimmed vacuoles (RVs), and sarcoplasmic inclusions containing ubiquitin and TDP-43 (TARDNA-binding protein 43). In this study, we find that IBMPFD muscle also accumulates autophagosome-associated proteins, Map1-LC3 (LC3), and p62/sequestosome, which localize to RVs. To test whether VCP participates in autophagy, we silenced VCP or expressed adenosine triphosphatase-inactive VCP. Under basal conditions, loss of VCP activity results in autophagosome accumulation. After autophagic induction, these autophagosomes fail to mature into autolysosomes and degrade LC3. Similarly, IBMPFD mutant VCP expression in cells and animals leads to the accumulation of nondegradative autophagosomes that coalesce at RVs and fail to degrade aggregated proteins. Interestingly, TDP-43 accumulates in the cytosol upon autophagic inhibition, similar to that seen after IBMPFD mutant expression. These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation.

A case of inclusion body myositis responsive to prednisolone therapy.

Inclusion body myositis, although rare, is the commonest cause of myopathy in patients aged over 50 years. The suggested pathogenesis remains uncertain and its prognosis remains poor. There have been select case reports of its association with an inflammatory etiology and it is postulated that this group of patients respond better to immunosuppressive therapy. We therefore report a rare case of inclusion body myositis that responded well to immunosuppressive therapy. We also report the possibility of its association with infliximab therapy.

Rabbits fed cholesterol-enriched diets exhibit pathological features of inclusion body myositis.

Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in humans; however, its etiology is unknown, there are few animal models for this disease, and effective treatments have not been identified. Similarities between pathological findings in Alzheimer's disease brain and IBM skeletal muscle include increased levels of amyloid precursor protein (APP) and amyloid beta-protein (Abeta). Moreover, there have been suggestions that elevated levels of free cholesterol might participate in the pathogenesis of Alzheimer's disease and IBM due, in part, to its role in Abeta generation. Here, we tested the hypothesis that rabbits fed cholesterol-enriched diets might faithfully exhibit human-like IBM pathological features. In skeletal muscle of one-third of the female rabbits fed cholesterol-enriched diet but not control diet, we found features of IBM, including vacuolated muscle fibers, increased numbers of mononuclear inflammatory cells, increased intramuscular deposition of Abeta, hyperphosphorylated tau, and increased numbers of muscle fibers immunopositive for ubiquitin. The cholesterol-enriched diet increased mRNA and protein levels of APP, increased the protein levels of betaAPP cleaving enzyme, and shifted APP processing in favor of Abeta production. Our study has demonstrated that increased ingestion of high levels of dietary cholesterol can result in pathological features that resemble IBM closely and thus may serve as an important new model with which to study this debilitating disorder.

[Inclusion body myositis after interferon-alpha treatment in a patient with HCV and HTLV-1 infection].

We report the first case of inclusion body myositis (IBM) which occurred after interferon-alpha treatment for chronic hepatitis C. A 63-year-old man contracted hepatitis C virus (HCV) and human T cell leukemia virus type 1 (HTLV-1) from a blood transfusion at age of 18. At age 57, he was treated with interferon-alpha (IFN alpha) for chronic hepatitis C. A month later, he developed muscle weakness in the proximal part of his lower extremities. IBM was diagnosed after a muscle biopsy at age 62. Steroid therapy improved his muscle power. One year later, worsening of his hepatic condition required re-administration of IFN alpha after gradual decrease and discontinuation of prednisolone. However, several days later, he rapidly became weaker and required a cane to walk. Elevated serum creatine kinase (2,199IU/L) and abnormal intensity in his MRI of thigh were demonstrated. The second muscle biopsy, performed after obtaining the informed consent from our patient, confirmed relapse of IBM. His symptoms improved again after discontinuation of IFN alpha and re-induction of prednisolone. Although a few cases each of IBM associated with HCV or HTLV-1 have been reported, the pathogenesis of virus-associated inflammatory myositis has not been clearly understood. Moreover, there has been no description on IBM associated with IFN alpha treatment, though several cases of polymyositis have been reported. Our case suggests that infection of HCV and HTLV-1 may be immunologically involved in the development of IBM and that IFN alpha can be directly related to onset and relapse of IBM.

Aluminum inclusion macrophagic myofasciitis: a recently identified condition.

The authors conclude that the persistence of aluminum hydroxide at the site of intramuscular injection is a novel finding which has an exact significance that remains to be established fully. It seems mandatory to evaluate possible long-term adverse effects induced by this compound, because this issue has not been addressed (in the past, aluminum hydroxide was believed to be cleared quickly from the body). If safety concerns about the long-term effects of aluminum hydroxide are confirmed, novel and alternative vaccine adjuvants to rescue vaccine-based strategies should be proposed to ensure the enormous benefit for public health that these vaccines provide worldwide.