Is Inclusion Body Myositis a Primary Degenerative Disease?
The mechanisms of pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's disease have been intensely investigated over the last several decades, and more recently, some of these mechanisms have been studied in IBM (Fig. 1). sIBM shares features with Alzheimer's disease including an association with aging and accumulation of amyloidogenic proteins. These pathologic features, along with the lack of responsiveness to steroids, have led to the hypothesis that sIBM is a primary degenerative disease with a secondary inflammatory response.[27•] However, there is an association of sIBM with specific HLA haplotypes, autoantibodies, and other autoimmune diseases. Furthermore, some patients have an overlap syndrome with polymyositis, and some sIBM patients with proximal limb weakness may be responsive to corticosteroids, at least early in the course of the disease. Thus, both the autoimmune and the degenerative hypotheses have merit, and both pathologic processes are likely involved in the progression of the disease.
Model for pathogenesis of sporadic inclusion body myositis – disruption of protein homeostasis
This model shows an interrelation of pathological hallmarks in sporadic inclusion body myositis (sIBM) including vacuoles, muscle atrophy, degeneration, accumulation of protein aggregates, and inflammation (shown in boxes). The consequences of aging (circled as the 'initiating' factor) include reactive oxygen species (ROS) and accumulation of ubiquitinated protein aggregates, degenerating mitochondria, and other macromolecules. In this model, these accumulations are both directly toxic to myofibers and also induce inflammation via induction of NF-κB. Protein aggregates are normally degraded via the ubiquitin–proteasome system (UPS) and autophagy, both of which are induced by the transcription factor FOXO. Growth factors such as IGF-1 stimulate protein synthesis and inhibit autophagy via the PI3K/Akt/TOR pathway to enable muscle growth. Disruption of autophagolysosome degradation may lead to accumulation of these structures as 'rimmed vacuoles' in sIBM patients. Thus, autophagy may be tightly regulated in muscle cells such that it is induced during cellular stress to allow degradation of toxic aggregates and inhibited during cell growth to allow synthesis of structural proteins.
One prominent hypothesis for the etiology of sIBM is that the disease is triggered by an accumulation of amyloid-beta peptide (Aβ), analogous to the amyloid hypothesis in Alzheimer's disease. In fact, a transgenic mouse 'model' of sIBM has been generated by overexpressing Aβ precursor protein (APP), and these mice are being used to study pathogenesis and new treatments for sIBM. In one such study, transgenic mice vaccinated with Aβ led to amelioration of the disease phenotype, prompting suggestions for a clinical trial of the vaccine in sIBM patients. However, the Aβ hypothesis is controversial,[31,32•] and many other proteins have been found to accumulate in sIBM muscle. It is unknown whether Aβ plays a role in the pathogenesis of sIBM or if it is merely one of many proteins that accumulate in diseased muscle.
Although the specific toxic molecule(s) that initiate the pathogenic cascade in IBM are unknown, oxidative stress associated with aging may trigger an accumulation of toxic macromolecules and organelles that is characteristic of IBM. As shown in Fig. 1, cells have several protective responses to these insults, such as upregulating chaperones to help refold misfolded proteins and inducing degradation of toxic compounds via autophagy or the ubiquitin–proteosome system (UPS) (reviewed in ). Furthermore, an accumulation of misfolded proteins within the endoplasmic reticulum (ER) causes an ER stress response that can trigger inflammation via NF-κB, induce autophagy, and suppress protein synthesis. Growth factors such as IGF-1 have the opposite effect via activation of the PI3K/Akt/Tor pathway. Thus, a complex homeostatic mechanism, similar to that seen in neurodegenerative diseases, regulates the cellular response to the deleterious effects of aging. The development of disease may be due to an imbalance in this homeostatic response triggering a feed-forward loop that leads to progressive degeneration.
One of the central questions in neurodegenerative diseases is whether ubiquitinated aggregates are toxic or beneficial; it may be different for each disease, but the leading hypothesis is that small oligomers are toxic and larger aggregates are likely cytoprotective. Primary targets for neurodegenerative disease therapy are agents that prevent protein aggregation. One class of proteins that function to prevent protein misfolding and aggregation are heat shock proteins, chaperones that are induced under conditions of cell stress. Arimoclomol is a drug that induces expression of heat shock proteins. In a mouse model of amyotrophic lateral sclerosis (ALS), arimoclomol slowed disease progression, prompting a clinical trial in ALS patients. A phase I safety trial of arimoclomol in ALS showed that it is well tolerated and safe. Phase II efficacy trials of arimoclomol are currently underway in sIBM and ALS and are expected to be completed soon.
Curr Opin Rheumatol. 2010;22(6):658-664. © 2010
Lippincott Williams & Wilkins
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