Novel Therapeutic Approaches for Inclusion Body Myositis

Thomas E. Lloyd


Curr Opin Rheumatol. 2010;22(6):658-664. 

In This Article

Is Inclusion Body Myositis Caused by Defective Autophagy?

One of the most intensively investigated fields of neurodegeneration research in recent years is that of autophagy. As shown in Fig. 2, autophagy is the cellular process whereby macromolecules or organelles are engulfed by a double-membrane 'phagophore' to form an 'autophagosome' that degrades the engulfed material upon fusion with the lysosome.[37,38] The rimmed vacuoles seen in IBM are believed to be an autophagolysosomal compartment.[39,40] Inhibition of autophagy in neurons is sufficient to cause ubiquitinated cytoplasmic aggregates and neurodegeneration.[41,42] Similarly, muscle-specific disruption of autophagy leads to muscle atrophy and accumulation of ubiquitinated aggregates, demonstrating that autophagy is critical for maintaining muscle mass.[43,44•]

Figure 2.

Role of autophagy in inclusion body myositis pathogenesis and potential therapeutic avenues
Myofiber degeneration in inclusion body myositis (IBM) is proposed to be due to toxic oligomers of misfolded proteins such as TDP-43. Arimoclomol is a drug being tried in IBM and neurodegenerative diseases due to its ability to induce expression of chaperones that help prevent accumulations of misfolded proteins. Normally, these ubiquitinated protein aggregates and damaged mitochondria (mitos) are degraded via the ubiquitin–proteasome system (UPS) or autophagy. Ubiquitinated aggregates may be recruited to the LC3 receptor on a newly forming double-membrane phagophore via the ubiquitin-binding protein p62/SQSTM1. Rapamycin and lithium both stimulate autophagy and help clear toxic aggregates such as TDP-43. VCP, mutated in familial IBM, functions in maturation of autophagosomes into an autophagolysosome. Overexpression of HDAC6 rescues the VCP phenotype, by stimulating autophagosome maturation. This step may be defective in sporadic inclusion body myositis (sIBM) as well, explaining the accumulation of rimmed vacuoles in addition to the numerous aggregated proteins. Upon fusion of autophagosomes with the lysosome, the ubiquinated aggregates and damaged mitochondria are degraded. A similar vacuolar pathology is seen in two rare inherited vacuolar myopathies in which myofiber degeneration is caused by defective lysosomal function termed XMEA (X-linked myopathy with 'excessive' autophagy, caused by loss of VMA21 function, required for lysosomal acidification) and Danon's disease (caused by mutations in lysosome-associated membrane protein 2 (LAMP2) involved in lysosome fusion).

Recently, Askanas and colleagues have shown that autophagy is defective in sIBM.[45••] They determined that activity of lysosomal enzymes Cathepsin B and D are reduced in IBM, and this defect is specific for IBM, as enzymatic activity is actually increased in polymyositis. Furthermore, the autophagosome marker LC3-II is upregulated specifically in sIBM, consistent with the increase in autophagolysosomes seen in IBM muscle. Similarly, Temiz et al.[28] showed that LC3 is the most frequent protein seen in aggregates in IBM and in polymyositis with mitochondrial disorder. Interestingly, the receptor for LC3 on autophagsomes, p62, a ubiquitin-binding protein, also forms prominent inclusions specifically in sIBM.[46•] Thus, the accumulation of rimmed vacuoles in IBM may be due to a defect in lysosomal degradation of autophagosomal material, and this in turn may lead to the accumulation of ubiquitinated aggregates and other toxic macromolecules. Nogalska et al.[45••] propose that the decreased lysosomal enzyme activity in IBM is due to ER stress, as experimentally induced ER stress in cultured muscle fibers leads to a similar reduction in lysosomal enzymatic activity. Similar accumulations of autophagosomes are seen in the vacuolar myopathies XMEA (X-linked myopathy with excessive autophagy) and Danon's disease, in which the defect is believed to be in lysosomal function.[47,48] Thus, a primary defect in autophagolysomal function can directly explain many of the pathological hallmarks of IBM, namely rimmed vacuoles, ubiquitinated aggregates, and muscle degeneration.

Further evidence for defective autophagy in IBM has come from the study of valosin-containing protein (VCP), mutated in the familial disease IBMPFD (IBM, Paget disease of bone, and frontotemporal dementia). Two independent studies have shown that VCP is essential for autophagy, and in its absence, rimmed vacuoles accumulate, suggesting that VCP is required for maturation of autophagosomes to autophagolysosomes.[49,50••] Interestingly, overexpression of HDAC6, a neuroprotective protein also involved in autophagosome maturation, rescues the cellular phenotype in this model.[51,52] In addition to ubiquitinated aggregates and rimmed vacuoles, a primary defect in autophagy in IBM can explain the accumulation of abnormal mitochondria in many patients, a characteristic feature of the disease.[53] Mitophagy, a specialized form of autophagy, is important for degrading degenerating mitochondria. Accumulation of damaged mitochondria may amplify oxidative stress associated with aging. A recent study may shed light on one potential link between mitochondrial degeneration and inflammation, whereby mitochondrial proteins released from dying cells activate the innate immune response due to their ancestral bacterial origin.[54,55]

Thus, stimulation of autophagy may accelerate the removal of toxic macromolecules and organelles in degenerative diseases. If autophagy is indeed defective in IBM, drugs that stimulate autophagy may be an important therapeutic intervention. Along this line, rapamycin (Sirolimus) may be a reasonable drug for clinical trials in IBM given its potent anti-inflammatory activity in addition to its ability to induce autophagy. Similarly, lithium is being tested in IBM, primarily for its ability to inhibit the kinase GSK-3 that phosphorylates tau and APP (phospho-tau is yet another abnormal inclusion in IBM), but it is also an inducer of autophagy.[56]

Although increasing autophagy may help clear toxic molecules, it may also lead to autophagic cell death or atrophy. One of the pathways for inducing muscle atrophy in cachexia and aging is the FOXO-mediated pathway that stimulates autophagy and the UPS.[57] These pathways are believed to be therapeutic targets for preventing age-associated muscle atrophy. Thus, too much or too little autophagy can lead to muscle atrophy.


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